Donate Help Contact The AHA Sign In Home
American Heart Association
Hypertension
Search: search_blue_button Advanced Search
Hypertension. 1997;29:366-370

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Griendling, K. K.
Right arrow Articles by Alexander, R. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Griendling, K. K.
Right arrow Articles by Alexander, R. W.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*L-TYROSINE

(Hypertension. 1997;29:366.)
© 1997 American Heart Association, Inc.


State-of-the-Art-Lecture

Angiotensin II Signaling in Vascular Smooth Muscle

New Concepts

Kathy K. Griendling; Masuko Ushio-Fukai; Bernard Lassègue; R. Wayne Alexander

From the Emory University School of Medicine, Division of Cardiology, Atlanta, Ga.

Correspondence to Kathy K. Griendling, PhD, Emory University, Division of Cardiology, 319 WMB, 1639 Pierce Dr, Atlanta, GA 30322. E-mail kgriend{at}emory.edu


*    Abstract
up arrowTop
*Abstract
down arrowIntroduction
down arrowEarly Signaling Events:...
down arrowTyrosine Phosphorylation
down arrowMAP Kinase Pathway
down arrowReceptor Desensitization and...
down arrowLong-term Signaling Events:...
down arrowDownregulation of Ang II...
down arrowConclusions
down arrowReferences
 
Angiotensin II is a multifunctional hormone that affects both contraction and growth of vascular smooth muscle cells through a complex series of intracellular signaling events initiated by the interaction of angiotensin II with the AT1 receptor. The cellular response to angiotensin II is multiphasic, involving stimulation within seconds of phospholipase C and Ca2+ mobilization; activation within minutes of phospholipase D, A2, protein kinase C, and MAP kinase; and stimulation after a period of hours of gene transcription and NADH/NADPH oxidase activity. Angiotensin II also activates numerous intracellular tyrosine kinases. In this respect, it shares some aspects of signaling with growth factor and cytokine receptors, including activation of phospholipase C-{gamma}, src, and ras; association of shc with grb2; and stimulation of the Jak/STAT pathway. The cellular events responsible for this unique series of events may involve receptor movement and the creation of a signaling domain. Elucidation of these pathways is important to our understanding of AT1 receptor function as a final effector of the renin-angiotensin system.


Key Words: angiotensin II • vascular smooth muscle • receptor sequestration • phospholipase • tyrosine • phosphorylation • oxidant stress

Abbreviations: Ang II = angiotensin II • AT1 = angiotensin type 1 receptor • GRK(s) = G protein-coupled receptor kinase(s) • MAP = mitogen-activated protein • PLA2, PLC, PLD = phospholipases A2, C, D • VSMC(s) = vascular smooth muscle cell(s)


*    Introduction
up arrowTop
up arrowAbstract
*Introduction
down arrowEarly Signaling Events:...
down arrowTyrosine Phosphorylation
down arrowMAP Kinase Pathway
down arrowReceptor Desensitization and...
down arrowLong-term Signaling Events:...
down arrowDownregulation of Ang II...
down arrowConclusions
down arrowReferences
 
Ang II is a multifunctional hormone that has pleiotropic effects on vascular smooth muscle. It was originally identified as an acute regulator of vasomotor tone1 and has since been shown to promote vascular hypertrophy2,3 and in some cases, hyperplasia.4 It also affects vascular cell migration5 and extracellular matrix production.6 As such, it plays an important role in the normal and pathological physiology of the vessel wall. Virtually all of the hemodynamic effects of ang II are mediated by the AT1 receptor, which was cloned simultaneously by two groups.7,8 The biochemical pathways that are activated upon stimulation of the AT1 receptor are complex, but recent work has provided new insights into the signaling mechanisms utilized by this system.


*    Early Signaling Events: Phospholipase Activation
up arrowTop
up arrowAbstract
up arrowIntroduction
*Early Signaling Events:...
down arrowTyrosine Phosphorylation
down arrowMAP Kinase Pathway
down arrowReceptor Desensitization and...
down arrowLong-term Signaling Events:...
down arrowDownregulation of Ang II...
down arrowConclusions
down arrowReferences
 
Ang II rapidly activates multiple phospholipases to hydrolyze membrane phospholipids and generate signaling molecules. In cultured VSMCs, PLC is activated within 5 seconds, hydrolyzing phosphatidylinositol 4,5-bisphosphate to inositol trisphosphate and diacylglycerol.9,10 This response is transient, returning toward baseline by 2 minutes. These second messengers in turn release calcium from internal stores and activate protein kinase C, leading to a cascade of protein phosphorylations that direct the subsequent response of the cell. Protein kinase C also serves as a negative-feedback regulator of PLC, since it is apparently responsible, at least in part, for terminating the PLC response.11

Recently the identity of the PLC that is coupled to AT1 receptors has come into question. Marrero et al12 showed that in VSMCs, ang II phosphorylates PLC-{gamma} and that incubation of cells with the tyrosine kinase inhibitor genistein nearly abolishes inositol trisphosphate formation. These results suggest that the AT1 receptor is coupled to PLC-{gamma} via a tyrosine phosphorylation mechanism. However, other data support the concept that ang II receptors are coupled to a G protein-linked PLC. Thus, in permeabilized VSMCs, GTP{gamma}S synergistically enhances ang IIinduced inositol trisphosphate generation.13 Furthermore, downregulation of G{alpha}q/11 by prolonged agonist incubation markedly abrogates the ability of ang II to stimulate PLC,14 implying that a G protein of the Gq family is involved in coupling the AT1 receptor to PLC. It is possible that a G protein-coupled tyrosine kinase is upstream of PLC-{gamma}, but it is also possible that another PLC isotype is involved. The identity of this putative G protein-coupled PLC is unclear, since the prototypical subtype, PLC-ß, is not found in VSMCs.12 A leading candidate is PLC-{delta}, which is robustly expressed in vascular tissue.15

Ang II also activates PLD, hydrolyzing phosphatidylcholine to choline and phosphatidic acid. In VSMCs, phosphatidic acid is rapidly converted to diacylglycerol by phosphatidic acid phosphohydrolase. PLD activation is subsequent to that of PLC: it is detectable at 1 to 2 minutes and remains elevated for as long as 1 hour.16 In contrast to the PLC response, PLD activation does not appear to desensitize significantly during this time period. This pathway is the most important source of phosphatidic acid and diacylglycerol and probably represents the major pathway by which protein kinase C remains activated. There are two major unresolved questions concerning the AT1 receptor and the PLD pathway. First, the mechanism by which the receptor couples to PLD is unknown. Smallmolecular-weight G proteins (arf, rho), pertussis toxinsensitive and -insensitive heterotrimeric G proteins, protein kinase C activation, and tyrosine phosphorylation have been variously suggested as coupling mechanisms.17 Recent data indicate that there is a family of PLD isoforms,18 which may explain the plethora of proposed coupling mechanisms. Our own data in VSMCs strongly suggest that a heterotrimeric G protein is involved (K.K.G. et al, unpublished data, 1997), although the identity of the G protein and even the responsible subunit remains to be determined. The second major issue concerning PLD is its function in VSMCs. It is without doubt the major source of diacylglycerol for activation of protein kinase C,16 but it is likely to have other functions as well. For growth factors such as platelet-derived growth factor, it has been suggested that PLD is integral to the growth response.19 In neutrophils, the phosphatidic acid that results from PLD serves to activate an NADPH oxidase.20 Although a similar oxidase is activated by ang II in VSMCs,21 a role for PLD in this response remains to be established.

In addition to PLC and PLD, ang II rapidly activates PLA2 to release free fatty acids such as arachidonate.22 PLA2 activity in response to ang II is evident within minutes and is sustained for at least 30 minutes. The arachidonic acid that is produced is then converted via cyclooxygenase to prostaglandins, via lipoxygenase to unstable hydroperoxy intermediates that go on to form the leukotrienes, hydroxyeicosatetraenoic acids and lipoxins, or via cytochrome P450 monooxygenase to epoxides, midchain cis/trans conjugated dienols, and C-19/C-20 alcohols. Natarajan et al23 have shown that the lipoxygenase pathway has a role in VSMC hypertrophy. In addition, our recent data suggest that arachidonic acid metabolites may be involved in activation of NADH/NADPH oxidase (see below), thus regulating the oxidative state of the cell.24


*    Tyrosine Phosphorylation
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowEarly Signaling Events:...
*Tyrosine Phosphorylation
down arrowMAP Kinase Pathway
down arrowReceptor Desensitization and...
down arrowLong-term Signaling Events:...
down arrowDownregulation of Ang II...
down arrowConclusions
down arrowReferences
 
Recently it has become apparent that ang II, like many growth factors, stimulates the phosphorylation of numerous proteins on tyrosine residues (Table). Several of these proteins have been identified, and it is clear that phosphorylation and dephosphorylation of specific tyrosinecontaining proteins are important signaling events. In one of the earliest reports of ang II-induced tyrosine phosphorylation in VSMCs, Tsuda et al25 demonstrated that at least nine proteins are phosphorylated by ang II on tyrosine. This phosphorylation was mimicked either by phorbol 12-myristate 13-acetate activation of protein kinase C or by addition of the calcium ionophore ionomycin, suggesting that tyrosine kinase activation is downstream of PLC and PLD. Subsequent reports have identified numerous additional proteins phosphorylated on tyrosine by ang II in both VSMCs and cardiac fibroblasts.12,25–32


View this table:
[in this window]
[in a new window]
 
Ang II-Stimulated Protein Phosphorylation in the Cardiovascular System

Several of these tyrosine-phosphorylated proteins deserve specific comment. Ang II has been shown to phosphorylate and activate pp60src.27,28,30 This is potentially quite important, because src activates several other molecules involved in intracellular signaling, including PLC-{gamma}, pp120, p125FAK, paxillin, JAK2, STAT1, G{alpha}, and caveolin.33–36 In addition, src-family kinases have been implicated in the G protein receptor-mediated phosphorylation of the adapter protein shc.37 shc proteins (p46, p56, and p66) are tyrosine phosphorylated by ang II, and this leads to association with Grb2 via its SH2 domain.27 In growth factor receptor systems, Grb2 associates with the SH3 domain of SOS, which serves as a guanine nucleotide exchange factor to activate p21ras.38 It is unclear whether a similar system is utilized by the AT1 receptor. Ang II also phosphorylates and activates Jak2 and Tyk2 (Fig 1), tyrosine kinases usually associated with cytokine receptors.39 In VSMCs, Jak apparently phosphorylates STATs 1, 2, and 3, albeit with different time courses. STAT1 and STAT2 phosphorylation in response to ang II is maximal by {approx} 15 minutes, while STAT3 phosphorylation is not detectable until 60 minutes.39 Upon phosphorylation, STATs form dimers that associate with p48 and are translocated to the nucleus where they activate gene transcription, suggesting a possible role for this pathway in the activation of early growth response genes by ang II. Finally, ang II phosphorylates the cytosolic focal adhesion kinase (FAK), causing its translocation to sites of focal adhesion with the extracellular matrix and phosphorylation of talin and paxillin,40,41 which may be involved in the regulation of cell morphology and movement. Thus, it seems clear that ang II activates multiple tyrosine kinase pathways in VSMCs that, by analogy with growth factors, are likely to be important in mediating the growth effects of ang II.



View larger version (13K):
[in this window]
[in a new window]
 
FIG 1. Stimulation of Jak/STAT pathway by ang II. Ang II has been shown to activate both Jak2 and Tyk2 by phosphorylation. These activated kinases then phosphorylate STAT{alpha}/ß and STAT2, which associate with p48 to form an active transcriptional complex.


*    MAP Kinase Pathway
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowEarly Signaling Events:...
up arrowTyrosine Phosphorylation
*MAP Kinase Pathway
down arrowReceptor Desensitization and...
down arrowLong-term Signaling Events:...
down arrowDownregulation of Ang II...
down arrowConclusions
down arrowReferences
 
MAP kinases comprise a superfamily of serine/threonine protein kinases involved in cell growth and differentiation, as well as in cell transformation.42 ERK1 (p44mapk) and ERK2 (p42mapk), the most well studied of the MAP kinases, are activated by dual phosphorylation on the threonine and tyrosine occurring in the motif TEY43 and in turn phosphorylate numerous cellular proteins, including MBP, pp90rsk, p62TCF, 4E-BP-1, cPLA2, c-jun, and PHAS-1.44 Since the initial identification of ERK1 and ERK2, several other members of the MAP kinase superfamily have been identified, including ERK3 isoforms, Jun N-terminal kinases/stress-activated protein kinases (JNK/SAPK), p38mapk, p57mapk, and BMK-1 (Big MAP kinase-1 or ERK5).

It is now well documented that ang II activates the MAP kinase pathway in VSMCs. ERK1 and ERK2 were among the first tyrosine-phosphorylated proteins to be identified in ang II-stimulated cells.25,29,45,46 MAP kinase activation by ang II in VSMCs appears to be transient with a peak around 2 to 5 minutes, although activity remains elevated above baseline for at least 60 minutes.45–47 Stimulation of MAP kinase is at least partially dependent on protein kinase C45 and apparently requires prior activation of a Ca2+dependent tyrosine kinase.47

Recent work has focused on the biochemical pathways leading to MAP kinase activation (Fig 2). The immediate activator of MAP kinase is MEK (MAP or ERK kinase), which is a dual-specificity kinase that phosphorylates ERK1 and ERK2 on both threonine and tyrosine.48 MEK in turn is activated when it is phosphorylated on serine by a MAP kinase kinase. At least three MAP kinase kinases have been identified, raf-1, c-mos, and MEK kinase,49 two of which (raf-1 and MEK kinase) are activated by ang II.29,50 raf-1 is stimulated by phosphorylation on threonine and serine and is recruited to the plasma membrane by the small-molecular-weight G-binding protein ras.51 It is at this point that our knowledge of the MAP kinase activation pathway becomes sketchy. The stimulation of ras by growth factor receptors is complex, involving receptor autophosphorylation and binding to the SH2 domain of the adaptor protein Grb2, which then binds to the guanine nucleotide exchange factor SOS via its SH3 domain.52 A similar pathway may be used by G protein-coupled receptors, except that the initial tyrosine kinase is a nonreceptor tyrosine kinase. This has been clearly shown for Gi-coupled receptors,53 and evidence is accumulating that some Gqcoupled receptors may utilize this pathway as well.54 The most proximal kinase activated by these receptors is unknown, but current data suggest that a member of the src kinase family, src itself, lyn, or syk, may be involved.54 It has also been postulated that PI3 kinase activation may be upstream of ras activation.55 The primary signal initiating this cascade has been proposed to involve a Ca2+-dependent protein kinase47 or the ß{gamma} subunits of a coupling G protein.37 With regard to this pathway, ang II has been shown to activate pp60src,28 to promote association of Grb and SOS,27 to activate ras,47 and to phosphorylate raf-129 and MEK,50 although the links between each of these events remain to be established.



View larger version (16K):
[in this window]
[in a new window]
 
FIG 2. Ang II-induced MAP kinase activation in vascular smooth muscle. This schematic shows biochemical events that have been proposed to be involved in MAP kinase activation in VSMCs. Dotted lines indicate links that have not yet been demonstrated. Ang II binds to its receptor and activates an src family kinase, either directly or via activation of PI3K. src kinase phosphorylates shc, which then associates with Grb2 and SOS to promote guanine nucleotide exchange on ras. There is some evidence that ras is also activated by an upstream Ca2+-dependent tyrosine kinase. ras activates raf-1, perhaps by recruiting it to the membrane. raf or some other unknown MAP kinase kinase phosphorylates MEK, which then phosphorylates MAP kinase. Known substrates for MAP kinase are indicated. Dephosphorylation of MAP kinase is accomplished by activation of MKP-1. indicates addition of a phosphate group to the amino acid indicated by its one-letter abbreviation; AT1R, angiotensin type1 receptor; PI3K, phosphatidylinositol 3-kinase; SH2, src homology 2 domain; SH3, src homology 3 domain; MEK, MAP kinase kinase; MEKK, MAP kinase kinase kinase; TK, tyrosine kinase; MBP, myelin basic protein; and MKP-1, MAP kinase phosphatase-1.

As noted above, MAP kinase activity in response to ang II is transient, raising the issue of the mechanism(s) responsible for signal termination. Inactivation appears to be achieved by dephosphorylation of MAP kinase. The phosphatase responsible for this event, MKP-1 (mitogen-activated protein kinase phosphatase-1), was originally isolated as a nonspecific tyrosine phosphatase (3CH134) and was subsequently shown to have high specificity for MAP kinase.56 Like MEK, MKP-1 has dual specificity: It dephosphorylates MAP kinase on both threonine and tyrosine.56 In VSMCs, inhibition of MKP-1 leads to sustained activation of MAP kinase in response to ang II, suggesting that it is this enzyme that is primarily responsible for the termination of the MAP kinase signal.57 MKP-1 expression in turn is stimulated by ang II, so that MKP-1 serves as a long-term negative-feedback regulator of this pathway.58 Termination of MAP kinase activity may also involve activation of protein kinase A.59 This mechanism, however, most likely results from inhibition of the events leading to MAP kinase activation. Specifically, it appears that activators of protein kinase A inhibit the activity of raf-1.60


*    Receptor Desensitization and Creation of Signaling Domains
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowEarly Signaling Events:...
up arrowTyrosine Phosphorylation
up arrowMAP Kinase Pathway
*Receptor Desensitization and...
down arrowLong-term Signaling Events:...
down arrowDownregulation of Ang II...
down arrowConclusions
down arrowReferences
 
It is somewhat paradoxical that the most intense focus on AT1A receptor coupling mechanisms in VSMCs has been on PLC activation, a response that, regardless of the isozyme involved, is markedly desensitized and attenuated in {approx}5 minutes. In contrast, ang II-stimulated PLD is robustly activated as long as it has been followed to date— {approx}1 hour. The mechanisms responsible for this selective desensitization to PLC are not entirely understood. Desensitization to PLC prominently and perhaps predominantly involves protein kinase C, since downregulation of protein kinase C results in prolonged stimulation of PLC.61 In contrast, PLD activity cannot be sustained in the absence of protein kinase C activation (K.K.G. et al, unpublished observations, 1997). Termination of the PLC response may also involve phosphorylation of the receptor by GRKs, which in the ß-adrenergic receptor system phosphorylate ligand-bound receptors, promoting the binding of arrestin and the consequent interruption of G protein-mediated signal transduction.62 The AT1A receptor has been shown to be phosphorylated on serine and tyrosine in response to ang II, with a peak at 20 minutes of ang II stimulation.63 Although the kinases responsible for this phosphorylation in vivo are not known, in HEK293 cells cotransfected with the AT1A receptor and GRK-2, -3, or -5, receptor phosphorylation is augmented.64 Overexpression of a dominant negative K220R mutant GRK2 and inhibition of protein kinase C both attenuated, in an additive fashion, ang IIinduced AT1A receptor phosphorylation,64 suggesting that not only are GRKs involved in receptor phosphorylation but that receptor phosphorylation may also be an additional mechanism by which protein kinase C desensitizes PLC. In contrast, PLD is stimulated by exogenous activators of protein kinase C, and signaling through the PLD pathway in response to ang II continues even when the receptor is phosphorylated.16,63 These observations suggest that the two responses, PLC and PLD, are independently regulated and that PLD activation is resistant to conventional mechanisms of desensitization.

A recent hypothesis developed to explain these disparate signaling events involves the creation of signaling domains by ang II. It has long been known that the ang II receptor internalizes rapidly upon binding of the ligand.65,66 In fact, it was originally proposed as a mechanism of desensitization. However, the AT1 receptor internalizes with a half-time of 1.5 minutes,65 whereas PLD signaling commences at about this time and continues for 1 hour.16 This simple observation has led to the proposal that the receptor moves within the plane of the membrane (Fig 3) to a specialized domain from which prolonged signals are generated. Anderson et al67 showed that AT1 receptors rapidly move to coated pits, which internalize as vesicles and fuse with lysosomes. Zhang et al68 found that AT1 receptors also move to noncoated pits, suggesting that there may be two internalization mechanisms. The recent identification of caveolae as membrane signaling domains associated with growth factor receptors69 raises the possibility that the noncoated pit regions in which AT1 receptors aggregate may represent similar signaling domains. This is a particularly attractive notion, in view of the apparent association of src with caveolae70 and the recent observation that AT1 receptors activate src.28



View larger version (103K):
[in this window]
[in a new window]
 
FIG 3. Sequestration of the AT1 receptor. VSMCs were exposed to vehicle or 100 nmol/L ang II for 2 minutes and then stained with AT1 receptor antibody. After counterstaining with Texas red, immunofluorescence was visualized with a confocal microscope at x60. In control cells, fluorescence is distributed across the cytoplasm and is intensified in the area of the nucleus where the cell is thickest. In ang II-stimulated cells, fluorescence has moved to the perinuclear region and has become concentrated in punctate regions on the edges of the cells.


*    Long-term Signaling Events: Modulation of the Oxidative State
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowEarly Signaling Events:...
up arrowTyrosine Phosphorylation
up arrowMAP Kinase Pathway
up arrowReceptor Desensitization and...
*Long-term Signaling Events:...
down arrowDownregulation of Ang II...
down arrowConclusions
down arrowReferences
 
Although much emphasis has been placed on the rapid, transient biochemical pathways stimulated by ang II, it is clear that ang II has prolonged effects on VSMCs. As mentioned previously, one of these is PLD, which remains activated for as long as the agonist is present.16 Another important tonic signaling pathway is activation of NADH/NADPH oxidase (Fig 4). This enzyme transfers electrons from NADH or NADPH to molecular oxygen, producing superoxide anion (·O2-). Ang II activation of the NADH/NADPH oxidase is delayed: It is first detectable after about 1 hour and is sustained for at least 24 hours.21 Importantly, when NADH/NADPH oxidase activity is inhibited, ang II-stimulated protein synthesis is also inhibited, implying that activation of this pathway is integral to the growth response.



View larger version (10K):
[in this window]
[in a new window]
 
FIG 4. The NADPH/NADH oxidase pathway stimulated by ang II. Ang II activates a membrane NADPH/NADH oxidase to produce ·O2-, which is converted by superoxide dismutase (SOD) to H2O2. Both of these species have been implicated in gene induction and cell growth.

The structure and activation mechanisms of the VSMC NADH/NADPH oxidase are unknown. Recent work suggests that ang II-stimulated production of arachidonic acid metabolites may be required for oxidase activation, although this pathway has not been fully elucidated.24 In terms of structure, there is some evidence that this enzyme is similar to the bactericidal neutrophil enzyme, which consists of five subunits: a 22-kD {alpha}-subunit (p22phox) and a glycosylated 91-kD ß-subunit (gp91phox), which together compose cytochrome b558, the electron transfer element; cytosolic components p47phox and p67phox; and a low-molecular-weight G protein, rac 1 or rac 2.71 We have recently shown that smooth muscle oxidase is a p22phox-based enzyme,72 but the presence of other subunits has not been demonstrated in VSMCs. Although VSMC oxidase shares some similarity to the neutrophil enzyme, it differs in several important aspects. First, vascular oxidase preferentially utilizes NADH rather than NADPH as a substrate for its activity, and its output is much lower than that of phagocytic oxidase.21,73,74 Second, the peak of the absorbance spectrum of the cytochrome component of vascular oxidase is shifted slightly to the left ({approx}553 nm).72 Finally, knockout of p22phox in vascular cells does not affect baseline NADH-mediated ·O2- production but only attenuates ang II-stimulated oxidase activity,72 suggesting that the p22phox-containing oxidase is an inducible protein that has little constitutive activity in untreated cells.

The ·O2- that is produced by NADH/NADPH oxidase is presumably rapidly converted by superoxide dismutase to H2O2. We have recently shown that 4 hours of ang II treatment leads to H2O2 accumulation in VSMCs and that this H2O2 is a consequence of activation of the p22phoxbased enzyme.72 This is important, because the altered redox state of the cell promotes lipid peroxidation, and both lipid hydroperoxides and H2O2 increase expression of several growth-related and inflammatory genes and activate intracellular signaling pathways. Of potential importance to the VSMC response to ang II is the activation of PLA2,75 MAP kinases,76 and ras,77 as well as the induction of c-fos78 and c-jun.79 There is some evidence that this pathway is not involved in ang II stimulation of the MAP kinase pathway,76 but in general, the role of reactive oxygen species in growth-related signal transduction is an unexplored area. It is possible that the redox state of the cell acts as a rheostat to modulate the activation of cellular signaling enzymes, such as protein kinase C and tyrosine kinases, and may also directly alter the activity of transcription factors. That reactive oxygen species have a role in VSMC growth is fairly clear. H2O2 stimulates VSMC proliferation,80 inhibition of NADH/NADPH oxidase attenuates ang II-induced hypertrophy,21,72 and treatment of VSMCs with antioxidants induces apoptosis.81 The precise mechanisms await further definition.


*    Downregulation of Ang II Responsiveness
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowEarly Signaling Events:...
up arrowTyrosine Phosphorylation
up arrowMAP Kinase Pathway
up arrowReceptor Desensitization and...
up arrowLong-term Signaling Events:...
*Downregulation of Ang II...
down arrowConclusions
down arrowReferences
 
Many investigators have observed a diminution of responsiveness (termed either tachyphylaxis, desensitization, or downregulation) to repeated applications of ang II.82 There is no doubt that prolonged exposure to ang II alters the signaling pathways involved in subsequent signal generation. In VSMCs, ang II downregulates its own receptor,83 decreases the amount of and coupling to G{alpha}q,14 and increases GRK5 mRNA and protein expression.84 The overall effect is an attenuation of responsiveness to ang II. Thus, there are fewer surface receptors to be stimulated, and those that are present are unable to couple to G{alpha}q, unable to activate PLC, are phosphorylated, and therefore become inactivated, by increased GRKs. It is clear that not only does ang II acutely affect intracellular signal generation, but also that it regulates expression of key components of the signaling pathways to modulate long-term responsiveness.


*    Conclusions
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowEarly Signaling Events:...
up arrowTyrosine Phosphorylation
up arrowMAP Kinase Pathway
up arrowReceptor Desensitization and...
up arrowLong-term Signaling Events:...
up arrowDownregulation of Ang II...
*Conclusions
down arrowReferences
 
Ang II is a unique hormone that generates complex signaling events in VSMCs. Not only does it activate classic G protein-coupled phospholipases, but it also activates some of the same tyrosine kinase pathways that are coupled to growth factor receptors. VSMCs respond to ang II multiphasically: PLC activation and Ca2+ mobilization occurs within seconds, PLD and protein kinase C activation occur within minutes, and modulation of NADH/NADH oxidase activity occur within hours. The end result, contraction, hypertrophy, or proliferation, is influenced by the phenotype of the cell but also almost certainly results from selective activation of these multiple pathways. The cellular events responsible for this unique series of events may involve receptor movement and creation of a signaling domain. Elucidation of these pathways is important to our understanding of AT1 receptor function as a final effector of the renin-angiotensin system.


*    Acknowledgments
 
This work was supported by NIH grants HL47557 and HL38206 (to R.W.A. and K.K.G.) from the National Heart, Lung, and Blood Institute, Bethesda, Md. We thank Barbara Merchant for editorial assistance and for preparing the figures.


*    References
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowEarly Signaling Events:...
up arrowTyrosine Phosphorylation
up arrowMAP Kinase Pathway
up arrowReceptor Desensitization and...
up arrowLong-term Signaling Events:...
up arrowDownregulation of Ang II...
up arrowConclusions
*References
 
1. Elliott DF, Peart WS. Amino acid sequence of a hypertensin. Nature. 1956; 177 : 527 –528.[Medline] [Order article via Infotrieve]

2. Geisterfer A, Peach MJ, Owens GK. Angiotensin II induces hypertrophy, not hyperplasia of cultured rat aortic smooth muscle cells. Circ Res. 1988; 62 : 749 –756.[Abstract/Free Full Text]

3. Berk BC, Vekshtein V, Gordon HM, Tsuda T. Angiotensin II-stimulated protein synthesis in cultured vascular smooth muscle cells. Hypertension. 1989; 13 : 305 –314.[Abstract/Free Full Text]

4. Campbell-Boswell M, Robertson A. Effects of angiotensin II and vasopressin on human smooth muscle cells in vitro. Exp Mol Pathol. 1981; 35 : 265 –276.[Medline] [Order article via Infotrieve]

5. Dubey RK, Jackson EK, Luscher TF. Nitric oxide inhibits angiotensin II-induced migration of rat aortic smooth muscle cells: role of cyclic nucleotides and angiotensin-1 receptors. J Clin Invest. 1995; 96 : 141 –149.[Medline] [Order article via Infotrieve]

6. Kato H, Suzuki H, Tajima S, et al. Angiotensin II stimulates collagen synthesis in cultured vascular smooth muscle cells. J Hypertens. 1991; 9 : 17 –22.[Medline] [Order article via Infotrieve]

7. Sasaki K, Yamano Y, Bardhan S, et al. Cloning and expression of a complementary DNA encoding a bovine adrenal angiotensin II type-1 receptor. Nature. 1991; 351 : 230 –233.[Medline] [Order article via Infotrieve]

8. Murphy TJ, Alexander RW, Griendling KK, Runge MS, Bernstein KE. Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor. Nature. 1991; 351 : 233 –236.[Medline] [Order article via Infotrieve]

9. Alexander RW, Brock TA, Gimbrone MA Jr, Rittenhouse SE. Angiotensin increases inositol trisphosphate and calcium in vascular smooth muscle. Hypertension. 1985; 7 : 447 –451.[Abstract/Free Full Text]

10. Griendling KK, Rittenhouse SE, Brock TA, Ekstein LS, Gimbrone MA Jr, Alexander RW. Sustained diacylglycerol formation from inositol phospholipids in angiotensin II-stimulated vascular smooth muscle cells. J Biol Chem. 1986; 261 : 5901 –5906.[Abstract/Free Full Text]

11. Brock TA, Rittenhouse SE, Powers CW, Ekstein LS, Gimbrone MA Jr, Alexander RW. Phorbol ester and 1-oleoyl-2-acetylglycerol inhibit angiotensin activation of phospholipase C in cultured vascular smooth muscle cells. J Biol Chem. 1985; 260 : 14158 –14162.[Abstract/Free Full Text]

12. Marrero MB, Paxton WG, Duff JL, Berk BC, Bernstcin KE. Angiotensin II stimulates tyrosine phosphorylation of phospholipase C-gamma 1 in vascular smooth muscle cells. J Biol Chem. 1994; 269 : 10935 –10939.[Abstract/Free Full Text]

13. Socorro L, Alexander RW, Griendling KK. Cholera toxin modulation of angiotensin II-stimulated inositol phosphate production in cultured vascular smooth muscle cells. Biochem J. 1990; 265 : 799 –807.[Medline] [Order article via Infotrieve]

14. Kai H, Fukui T, Lassegue B, Shah A, Minieri CA, Griendling KK. Prolonged exposure to agonist results in a reduction in the levels of the Gq/G11 {alpha}-subunits in cultured vascular smooth muscle cells. Mol Pharmacol. 1996; 49 : 96 –104.[Abstract]

15. Homma Y, Sakamoto H, Tsunoda M, Aoki M, Takenawa T, Ooyama T. Evidence for involvement of phospholipase C-gamma 2 in signal transduction of platelet-derived growth factor in vascular smooth muscle cells. Biochem J. 1993; 290 : 649 –653.[Medline] [Order article via Infotrieve]

16. Lassegue B, Alexander RW, Clark M, Akers MA, Griendling KK. Phosphatidylcholine is a major source of phosphatidic acid and diacylglycerol in angiotensin II-stimulated vascular smooth muscle cells. Biochem J. 1993; 292 : 509 –517.[Medline] [Order article via Infotrieve]

17. Exton J. Phosphatidylcholine breakdown and signal transduction. Biochim Biophys Acta. 1994; 1212 : 26 –42.[Medline] [Order article via Infotrieve]

18. Hammond SM, Altshuller YM, Sung T-C, et al. Human ADP-ribosylation factor-activated phosphatidylcholine-specific phospholipase D defines a new and highly conserved gene family. J Biol Chem. 1995; 270 : 29640 –29643.[Abstract/Free Full Text]

19. Kondo T, Inui H, Konishi F, Inagami T. Phospholipase D mimics platelet-derived growth factor as a competence factor in vascular smooth muscle cells. J Biol Chem. 1992; 267 : 23609 –23616.[Abstract/Free Full Text]

20. Bellavite P, Corso F, Dusi S, Grzeskowiak M, Della-Bianca V, Rossi F. Activation of NADPH-dependent superoxide production in plasma membrane extracts of pig neutrophils by phosphatidic acid. J Biol Chem. 1988; 263 : 8210 –8214.[Abstract/Free Full Text]

21. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994; 74 : 1141 –1148.[Abstract/Free Full Text]

22. Rao GN, Lassegue B, Alexander RW, Griendling KK. Angiotensin II stimulates phosphorylation of high-molecular-mass cytosolic phospholipase A2 in vascular smooth-muscle cells. Biochem J. 1994; 299 : 197 –201.[Medline] [Order article via Infotrieve]

23. Natarajan R, Gonzales N, Hornsby PJ, Nadler J. Mechanisms of angiotensin II-induced proliferation in bovine adrenocortical cells. Endocrinology. 1992; 131 : 1174 –1180.[Abstract/Free Full Text]

24. Zafari AM, Alexander RW, Minieri C, Akers M, Lassegue B, Griendling KK. Arachidonic acid metabolites mediate angiotensin II-induced hypertrophy by stimulation of NADH/NADPH oxidase activity in cultured vascular smooth muscle cells. FASEB J. 1996; 10 : A1013 . Abstract.

25. Tsuda T, Kawahara Y, Shii K, Koide M, Ishida Y, Yokoyama M. Vasoconstrictor-induced protein-tyrosine phosphorylation in cultured vascular smooth muscle cells. FEBS Lett. 1991; 285 : 44 –48.[Medline] [Order article via Infotrieve]

26. Du J, Sperling LS, Marrero MB, Phillips L, Delafontaine P. G-protein and tyrosine kinase receptor cross-talk in rat aortic smooth muscle cells: thrombin and angiotensin II-induced tyrosine phosphorylation of insulin receptor substrate-1 and insulin-like growth factor 1 receptor. Biochem Biophys Res Commun. 1996; 218 : 934 –939.[Medline] [Order article via Infotrieve]

27. Linseman DA, Benjamin CW, Jones DA. Convergence of angiotensin II and platelet-derived growth factor receptor signaling cascades in vascular smooth muscle cells. J Biol Chem. 1995; 270 : 12563 –12568.[Abstract/Free Full Text]

28. Ishida M, Marrero MB, Schieffer B, Ishida T, Bernstein KE, Berk BC. Angiotensin II activates pp60c-src in vascular smooth muscle cells. Circ Res. 1995; 77 : 1053 –1059.[Abstract/Free Full Text]

29. Molloy CJ, Taylor DS, Weber H. Angiotensin II stimulation of rapid protein tyrosine phosphorylation and protein kinase activation in rat aortic smooth muscle cells. J Biol Chem. 1993; 268 : 7338 –7345.[Abstract/Free Full Text]

30. Butcher RD, Schollmann C, Marme D. Angiotensin II mediates intracellular signaling in vascular smooth muscle cells by activation of tyrosine-specific kinases and c-raf-1. Biochem Biophys Res Commun. 1993; 196 : 1280 –1287.[Medline] [Order article via Infotrieve]

31. Schorb W, Peeler TC, Madigan NN, Conrad KM, Baker KM. Angiotensin II-induced protein tyrosine phosphorylation in neonatal rat cardiac fibroblasts. J Biol Chem. 1994; 269 : 19626 –19632.[Abstract/Free Full Text]

32. Leduc I, Meloche S. Angiotensin II stimulates tyrosine phosphorylation of the focal adhesion-associated protein paxillin in aortic smooth muscle cells. J Biol Chem. 1995; 270 : 4401 –4404.[Abstract/Free Full Text]

33. Akiho H, Tokumitsu Y, Noda M, Nomura Y. Decreases in coupling of Gs in v-src transformed NIH-3T3 fibroblasts: possible involvement of tyrosine phosphorylation of Gs by pp60v-src. Arch Biochem Biophys. 1993; 304 : 235 –241.[Medline] [Order article via Infotrieve]

34. Li S, Seitz R, Lisanti MP. Phosphorylation of caveolin by src tyrosine kinases: the alpha-isoform of caveolin is selectively phosphorylated by v-src in vivo. J Biol Chem. 1996; 271 : 3863 –3868.[Abstract/Free Full Text]

35. Marrero MB, Schieffer B, Paxton WG, Schieffer E, Bernstein KE. Electroporation of pp60c-src antibodies inhibits the angiotensin II activation of phospholipase C-{gamma}1 in rat aortic smooth muscle cells. J Biol Chem. 1995; 270 : 15734 –15738.[Abstract/Free Full Text]

36. Schieffer B, Paxton WG, Marrero MB, Bernstein KE. Importance of tyrosine phosphorylation in angiotensin II type 1 receptor signaling. Hypertension. 1996; 27 : 476 –480.[Abstract/Free Full Text]

37. Touhara K, Hawes BE, Van Biesen T, Lefkowitz RJ. G protein ß{gamma} subunits stimulate phosphorylation of shc adapter protein. Proc Natl Acad Sci U S A. 1995; 92 : 9284 –9287.[Abstract/Free Full Text]

38. Pronk GJ, de Vries-Smits AMM, Buday L, et al. Involvement of Shc in insulin- and epidermal growth factor-induced activation of p21ras. Mol Cell Biol. 1994; 14 : 1575 –1581.[Abstract/Free Full Text]

39. Marrero MB, Schieffer B, Paxton WG, et al. Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor. Nature. 1995; 375 : 247 –250.[Medline] [Order article via Infotrieve]

40. Schaller MD, Parsons JT. Focal adhesion kinase: an integrin linked protein tyrosine kinase. Trends Cell Biol. 1993; 3 : 258 –261.[Medline] [Order article via Infotrieve]

41. Turner CE, Pietras KM, Taylor DS, Molloy CJ. Angiotensin II stimulation of rapid paxillin tyrosine phosphorylation correlates with the formation of focal adhesions in rat aortic smooth muscle cells. J Cell Sci. 1995; 108 : 333 –342.[Abstract]

42. Boulton TG, Nye SH, Robbins DJ, et al. ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell. 1991; 65 : 663 –675.[Medline] [Order article via Infotrieve]

43. Payne DM, Rossomando AJ, Martino P, et al. Identification of the regulatory phosphorylation sites in pp42/mitogen activated protein kinase (MAP kinase). EMBO J. 1991; 10 : 885 –892.[Medline] [Order article via Infotrieve]

44. Duff JL, Marrero MB, Paxton WG, Schieffer B, Bernstein KE, Berk BC. Angiotensin II signal transduction and the mitogen-activated protein kinase pathway. Cardiovas Res. 1995; 30 : 511 –517.[Medline] [Order article via Infotrieve]

45. Tsuda T, Kawahara Y, Ishida Y, Koide M, Shii K, Yokoyama M. Angiotensin II stimulates two myelin basic protein/microtubule-associated protein 2 kinases in cultured vascular smooth muscle cells. Circ Res. 1992; 71 : 620 –630.[Abstract/Free Full Text]

46. Duff JL, Berk BC, Corson MA. Angiotensin II stimulates the pp44 and pp42 mitogen activated protein kinases in cultured rat aortic smooth muscle cells. Biochem Biophys Res Commun. 1992; 188 : 257 –264.[Medline] [Order article via Infotrieve]

47. Eguchi S, Matsumoto T, Motley ED, Utsunomiya H, Inagami T. Identification of an essential signaling cascade for mitogen-activated protein kinase activation by angiotensin II in cultured rat vascular smooth muscle cells. J Biol Chem. 1996; 271 : 14169 –14175.[Abstract/Free Full Text]

48. Crews CM, Alessandrini A, Erickson RL. The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. Science. 1992; 258 : 478 –480.[Abstract/Free Full Text]

49. Davis RJ. Transcriptional regulation by MAP kinases. Mol Reprod Dev. 1995; 42 : 459 –467.[Medline] [Order article via Infotrieve]

50. Ishida Y, Kawahara Y, Tsuda T, Yokoyama M. Involvement of MAP kinase activators in angiotensin II-induced activation of MAP kinases in cultured vascular smooth muscle cells. FEBS Lett. 1992; 310 : 41 –45.[Medline] [Order article via Infotrieve]

51. Leevers SJ, Paterson HF, Marshall CJ. Requirement for ras in raf activation is overcome by targeting raf to the plasma membrane. Nature. 1994; 369 : 411 –414.[Medline] [Order article via Infotrieve]

52. Lowenstein EJ, Daly RJ, Betzer AG, et al. The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell. 1992; 70 : 431 –442.[Medline] [Order article via Infotrieve]

53. van Biesen T, Hawes BE, Luttrell DK, et al. Receptor-tyrosine-kinase- and Gbg-mediated MAP kinase activation by a common signaling pathway. Nature. 1995; 376 : 781 –784.[Medline] [Order article via Infotrieve]

54. Wan Y, Kurosaki T, Huang X-Y. Tyrosine kinases in activation of the MAP kinase cascade by G-protein-coupled receptors. Nature. 1996; 380 : 541 –544.[Medline] [Order article via Infotrieve]

55. Hawes BE, Luttrell LM, van Biesen T, Lefkowitz RJ. Phosphatidylinositol 3-kinase is an early intermediate in the Gbg-mediated mitogen activated protein kinase signaling pathway. J Biol Chem. 1996; 271 : 12133 –12136.[Abstract/Free Full Text]

56. Sun H, Charles CH, Lau LF, Tonks NK. MKP-1 (3CH134), an early immediate gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo. Cell. 1993; 75 : 487 –493.[Medline] [Order article via Infotrieve]

57. Duff JL, Monia BP, Berk BC. Mitogen-activated protein (MAP) kinase is regulated by the MAP kinase phosphatase (MKP-1) in vascular smooth muscle cells. J Biol Chem. 1995; 270 : 7161 –7166.[Abstract/Free Full Text]

58. Duff JL, Marrero MB, Paxton WG, et al. Angiotensin II induces 3CH134, a protein tyrosine phosphatase, in vascular smooth muscle cells. J Biol Chem. 1993; 268 : 26037 –26040.[Abstract/Free Full Text]

59. Wu J, Dent P, Jelinek T, Wolfman A, Weber MJ, Sturgill TW. Inhibition of the EGF-activated MAP kinase signaling pathway by adenosine 3',5'-monophosphate. Science. 1993; 262 : 1065 –1069.[Abstract/Free Full Text]

60. Cook SJ, McCormick F. Inhibition by cAMP of ras-dependent activation of raf. Science. 1993; 262 : 1069 –1072.[Abstract/Free Full Text]

61. Pfeilschifter J, Bauer C. Different effects of phorbol ester on angiotensin II- and stable GTP analogue-induced activation of polyphosphoinositide phosphodiesterase in membranes isolated from rat renal mesangial cells. Biochem J. 1987; 248 : 209 –215.[Medline] [Order article via Infotrieve]

62. Lefkowitz RJ. G-protein coupled receptor kinases. Cell. 1993; 74 : 409 –412.[Medline] [Order article via Infotrieve]

63. Kai H, Griendling KK, Lassegue B, Ollerenshaw JD, Runge MS, Alexander RW. Agonist-induced phosphorylation of the vascular type 1 angiotensin II receptor. Hypertension. 1994; 24 : 523 –527.[Abstract/Free Full Text]

64. Oppermann M, Freedman NJ, Alexander RW, Lefkowitz RJ. Phosphorylation of the type 1A angiotensin II receptor by G protein-coupled receptor kinases and protein kinase C. J Biol Chem. 1996; 271 : 13266 –13272.[Abstract/Free Full Text]

65. Griendling KK, Delafontaine P, Rittenhouse SE, Gimbrone MA Jr, Alexander RW. Correlation of receptor sequestration with sustained diacylglycerol accumulation in angiotensin II-stimulated cultured vascular smooth muscle cells. J Biol Chem. 1987; 262 : 14555 –14562.[Abstract/Free Full Text]

66. Peach MJ. Molecular actions of angiotensin. Biochem Pharmacol. 1981; 30 : 2745 –2751.[Medline] [Order article via Infotrieve]

67. Anderson KM, Murahashi T, Dostal DE, Peach MJ. Morphological and biochemical analysis of angiotensin II internalization in cultured rat aortic smooth muscle cells. Am J Physiol. 1993; 264 : C179 –C188.[Medline] [Order article via Infotrieve]

68. Zhang J, Ferguson SSG, Barak LS, Ménard L, Caron MG. Dynamin and beta-arrestin reveal distinct mechanisms for G-protein coupled receptor internalization. J Biol Chem. 1996; 271 : 18302 –18305.[Abstract/Free Full Text]

69. Liu P, Ying Y, Ko Y, Anderson RGW. Localization of platelet-derived growth factor-stimulated phosphorylation cascade to caveolae. J Biol Chem. 1996; 271 : 10299 –10303.[Abstract/Free Full Text]

70. Shenoy-Scaria AM, Dietzen DJ, Kwong J, Link DC, Lublin DM. Cysteine3 of Src family protein tyrosine kinase determines palmitoylation and localization in caveolae. J Cell Biol. 1994; 126 : 353 –363.[Abstract/Free Full Text]

71. Jones OTG. The regulation of superoxide production by the NADPH oxidase of neutrophils and other mammalian cells. Bioessays. 1994; 16 : 919 –923.[Medline] [Order article via Infotrieve]

72. Ushio-Fukai M, Zafari AM, Fukui T, Ishizaka N, Griendling KK. p22phox is a critical component of the superoxide-generating NADH/ NADPH oxidase system and regulates angiotensin II-induced hypertrophy in vascular smooth muscle cells. J Biol Chem. 1996; 271 : 23317 –23321.[Abstract/Free Full Text]

73. Mohazzab KM, Wolin MS. Sites of superoxide anion production detected by lucigenin in calf pulmonary artery smooth muscle. Am J Physiol. 1994; 267 : L815 –L822.[Medline] [Order article via Infotrieve]

74. Rajagopalan S, Kurz S, Münzel T, et al. Angiotensin II mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone. J Clin Invest. 1996; 97 : 1916 –1923.[Medline] [Order article via Infotrieve]

75. Rao GN, Runge MS, Alexander RW. Hydrogen peroxide activation of cytosolic phospholipase A2 in vascular smooth muscle cells. Biochim Biophys Acta. 1995; 1265 : 67 –72.[Medline] [Order article via Infotrieve]

76. Baas AS, Berk BC. Differential activation of mitogen-activated protein kinases by H2O2 and O2- in vascular smooth muscle cells. Circ Res. 1995; 77 : 29 –36.[Abstract/Free Full Text]

77. Rao GN. Hydrogen peroxide induces complex formation of SHC-Grb2-SOS with receptor tyrosine kinase and activates ras and extra-cellular signal-regulated protein kinases group of mitogen activated protein kinases. Oncogene. 1996; 13 : 713 –719.[Medline] [Order article via Infotrieve]

78. Rao GN, Lassegue B, Griendling KK, Alexander RW, Berk BC. Hydrogen peroxide-induced c-fos expression is mediated by arachidonic acid release: role of protein kinase C. Nucleic Acids Res. 1993; 21 : 1259 –1263.[Abstract/Free Full Text]

79. Rao GN, Lassegue B, Griendling KK, Alexander RW. Hydrogen peroxide stimulates transcription of c-jun in vascular smooth muscle cells: role of arachidonic acid. Oncogene. 1993; 8 : 2759 –2764.[Medline] [Order article via Infotrieve]

80. Rao GN, Berk BC. Active oxygen species stimulate vascular smooth muscle cell growth and proto-oncogene expression. Circ Res. 1992; 70 : 593 –599.[Abstract/Free Full Text]

81. Tsai J-C, Jain M, Hsieh C-M, et al. Induction of apoptosis by pyrrolidinedithiocarbamate and N-acetylcysteine in vascular smooth muscle cells. J Biol Chem. 1996; 271 : 3667 –3670.[Abstract/Free Full Text]

82. Peach MJ. Renin-angiotensin system: biochemistry and mechanisms of action. Physiol Rev. 1977; 57 : 313 –370.[Free Full Text]

83. Lassègue B, Alexander RW, Nickenig G, Clark M, Murphy TJ, Griendling KK. Angiotensin II down-regulates the vascular AT1 receptor by transcriptional and post-transcriptional mechanisms: evidence for homologous and heterologous regulation. Mol Pharmacol. 1995; 48 : 601 –609.[Abstract]

84. Ishizaka N, Griendling KK, Fukui T, Oppermann M, Lefkowitz RJ, Alexander RW. Functional interaction between angiotensin II and GRK5 in cultured vascular smooth muscle cells (VSMC) and rat aorta. FASEB J. 1996; 10 A1134 . Abstract.

85. Paxton WG, Marrero MB, Klein JD, Delafontaine P, Berk BC, Bernstein KE. The angiotensin II AT1 receptor is tyrosine and serine phosphorylated and can serve as a substrate for the src family of tyrosine kinases. Biochem Biophys Res Commun. 1994; 200 : 260 –267.[Medline] [Order article via Infotrieve]

86. Polte TR, Naftilan AJ, Hanks SK. Focal adhesion kinase is abundant in developing blood vessels and elevation of its phosphotyrosine content in vascular smooth muscle cells is a rapid response to angiotensin II. J Cell Biochem. 1994; 55 : 106 –119.[Medline] [Order article via Infotrieve]




This article has been cited by other articles:


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
S. Amirbekian, R. C. Long Jr., M. A. Consolini, J. Suo, N. J. Willett, S. W. Fielden, D. P. Giddens, W. R. Taylor, and J. N. Oshinski
In vivo assessment of blood flow patterns in abdominal aorta of mice with MRI: implications for AAA localization
Am J Physiol Heart Circ Physiol, October 1, 2009; 297(4): H1290 - H1295.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
A. K. Stennett, X. Qiao, A. E. Falone, V. V. Koledova, and R. A. Khalil
Increased vascular angiotensin type 2 receptor expression and NOS-mediated mechanisms of vascular relaxation in pregnant rats
Am J Physiol Heart Circ Physiol, March 1, 2009; 296(3): H745 - H755.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
I. K. Mohan, M. Khan, S. Wisel, K. Selvendiran, A. Sridhar, C. A. Carnes, B. Bognar, T. Kalai, K. Hideg, and P. Kuppusamy
Cardioprotection by HO-4038, a novel verapamil derivative, targeted against ischemia and reperfusion-mediated acute myocardial infarction
Am J Physiol Heart Circ Physiol, January 1, 2009; 296(1): H140 - H151.
[Abstract] [Full Text] [PDF]


Home page
EndocrinologyHome page
H. Ohtsu, S. Higuchi, H. Shirai, K. Eguchi, H. Suzuki, A. Hinoki, E. Brailoiu, A. D. Eckhart, G. D. Frank, and S. Eguchi
Central Role of Gq in the Hypertrophic Signal Transduction of Angiotensin II in Vascular Smooth Muscle Cells
Endocrinology, July 1, 2008; 149(7): 3569 - 3575.
[Abstract] [Full Text] [PDF]


Home page
Nucleic Acids ResHome page
E. Sanchez-Guerrero, V. C. Midgley, and L. M. Khachigian
Angiotensin II induction of PDGF-C expression is mediated by AT1 receptor-dependent Egr-1 transactivation
Nucleic Acids Res., April 1, 2008; 36(6): 1941 - 1951.
[Abstract] [Full Text] [PDF]


Home page
Anesth. Analg.Home page
A. Ishikawa, K. Ogawa, Y. Tokinaga, N. Uematsu, K. Mizumoto, and Y. Hatano
The Mechanism Behind the Inhibitory Effect of Isoflurane on Angiotensin II-Induced Vascular Contraction Is Different from That of Sevoflurane
Anesth. Analg., July 1, 2007; 105(1): 97 - 102.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
F. A. Yaghini, F. Li, and K. U. Malik
Expression and Mechanism of Spleen Tyrosine Kinase Activation by Angiotensin II and Its Implication in Protein Synthesis in Rat Vascular Smooth Muscle Cells
J. Biol. Chem., June 8, 2007; 282(23): 16878 - 16890.
[Abstract] [Full Text] [PDF]


Home page
Physiol. Rev.Home page
L. Oliveira, C. M. Costa-Neto, C. R. Nakaie, S. Schreier, S. I. Shimuta, and A. C. M. Paiva
The Angiotensin II AT1 Receptor Structure-Activity Correlations in the Light of Rhodopsin Structure
Physiol Rev, April 1, 2007; 87(2): 565 - 592.
[Abstract] [Full Text] [PDF]


Home page
HypertensionHome page
M. Ushio-Fukai and R. W. Alexander
Caveolin-Dependent Angiotensin II Type 1 Receptor Signaling in Vascular Smooth Muscle
Hypertension, November 1, 2006; 48(5): 797 - 803.
[Full Text] [PDF]


Home page
HypertensionHome page
H. Ohtsu, H. Suzuki, H. Nakashima, S. Dhobale, G. D. Frank, E. D. Motley, and S. Eguchi
Angiotensin II Signal Transduction Through Small GTP-Binding Proteins: Mechanism and Significance in Vascular Smooth Muscle Cells
Hypertension, October 1, 2006; 48(4): 534 - 540.
[Full Text] [PDF]


Home page
Chem SensesHome page
R. N. Thompson, A. Napier, and K. S. Wekesa
Attenuation of the Production of Inositol 1,4,5-Trisphosphate in the Mouse Vomeronasal Organ by Antibodies Against the {alpha}q/11 Subfamily of G-Proteins
Chem Senses, September 1, 2006; 31(7): 613 - 619.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
H. Ohtsu, P. J. Dempsey, G. D. Frank, E. Brailoiu, S. Higuchi, H. Suzuki, H. Nakashima, K. Eguchi, and S. Eguchi
ADAM17 Mediates Epidermal Growth Factor Receptor Transactivation and Vascular Smooth Muscle Cell Hypertrophy Induced by Angiotensin II
Arterioscler Thromb Vasc Biol, September 1, 2006; 26(9): e133 - e137.
[Abstract] [Full Text] [PDF]


Home page
Mol. Endocrinol.Home page
D. K. Yee, A. Suzuki, L. Luo, and S. J. Fluharty
Identification of Structural Determinants for G Protein-Independent Activation of Mitogen-Activated Protein Kinases in the Seventh Transmembrane Domain of the Angiotensin II Type 1 Receptor
Mol. Endocrinol., August 1, 2006; 20(8): 1924 - 1934.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Cell Physiol.Home page
H. Ohtsu, P. J. Dempsey, and S. Eguchi
ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors
Am J Physiol Cell Physiol, July 1, 2006; 291(1): C1 - C10.
[Abstract] [Full Text] [PDF]


Home page
J. Pharmacol. Exp. Ther.Home page
V. K. Kutala, M. Khan, R. Mandal, L. P. Ganesan, S. Tridandapani, T. Kalai, K. Hideg, and P. Kuppusamy
Attenuation of Myocardial Ischemia-Reperfusion Injury by Trimetazidine Derivatives Functionalized with Antioxidant Properties
J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 921 - 928.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
A. Douillette, A. Bibeau-Poirier, S.-P. Gravel, J.-F. Clement, V. Chenard, P. Moreau, and M. J. Servant
The Proinflammatory Actions of Angiotensin II Are Dependent on p65 Phosphorylation by the I{kappa}B Kinase Complex
J. Biol. Chem., May 12, 2006; 281(19): 13275 - 13284.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Cell Physiol.Home page
E. A. Woolfolk, S. Eguchi, H. Ohtsu, H. Nakashima, H. Ueno, W. T. Gerthoffer, and E. D. Motley
Angiotensin II-induced activation of p21-activated kinase 1 requires Ca2+ and protein kinase C{delta} in vascular smooth muscle cells
Am J Physiol Cell Physiol, November 1, 2005; 289(5): C1286 - C1294.
[Abstract] [Full Text] [PDF]


Home page
HypertensionHome page
R. M.P. Arruda, V. A. Peotta, S. S. Meyrelles, and E. C. Vasquez
Evaluation of Vascular Function in Apolipoprotein E Knockout Mice With Angiotensin-Dependent Renovascular Hypertension
Hypertension, October 1, 2005; 46(4): 932 - 936.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
H. Ohtsu, M. Mifune, G. D. Frank, S. Saito, T. Inagami, S. Kim-Mitsuyama, Y. Takuwa, T. Sasaki, J. D. Rothstein, H. Suzuki, et al.
Signal-Crosstalk Between Rho/ROCK and c-Jun NH2-Terminal Kinase Mediates Migration of Vascular Smooth Muscle Cells Stimulated by Angiotensin II
Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1831 - 1836.
[Abstract] [Full Text] [PDF]


Home page
Anesth. Analg.Home page
J. Yu, K. Mizumoto, Y. Tokinaga, K. Ogawa, and Y. Hatano
The Inhibitory Effects of Sevoflurane on Angiotensin II- Induced, p44/42 Mitogen-Activated Protein Kinase-Mediated Contraction of Rat Aortic Smooth Muscle
Anesth. Analg., August 1, 2005; 101(2): 315 - 321.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
M. Mifune, H. Ohtsu, H. Suzuki, H. Nakashima, E. Brailoiu, N. J. Dun, G. D. Frank, T. Inagami, S. Higashiyama, W. G. Thomas, et al.
G Protein Coupling and Second Messenger Generation Are Indispensable for Metalloprotease-dependent, Heparin-binding Epidermal Growth Factor Shedding through Angiotensin II Type-1 Receptor
J. Biol. Chem., July 15, 2005; 280(28): 26592 - 26599.
[Abstract] [Full Text] [PDF]


Home page
Biol. Reprod.Home page
J. Zheng, Y. Wen, D.-b. Chen, I. M. Bird, and R. R. Magness
Angiotensin II Elevates Nitric Oxide Synthase 3 Expression and Nitric Oxide Production Via a Mitogen-Activated Protein Kinase Cascade in Ovine Fetoplacental Artery Endothelial Cells
Biol Reprod, June 1, 2005; 72(6): 1421 - 1428.
[Abstract] [Full Text] [PDF]


Home page
J. Physiol.Home page
J. Zheng, I. M. Bird, D.-B. Chen, and R. R. Magness
Angiotensin II regulation of ovine fetoplacental artery endothelial functions: interactions with nitric oxide
J. Physiol., May 15, 2005; 565(1): 59 - 69.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
R. P. Brandes and J. Kreuzer
Vascular NADPH oxidases: molecular mechanisms of activation
Cardiovasc Res, January 1, 2005; 65(1): 16 - 27.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
M. Ishibashi, K. Egashira, Q. Zhao, K.-i. Hiasa, K. Ohtani, Y. Ihara, I. F. Charo, S. Kura, T. Tsuzuki, A. Takeshita, et al.
Bone Marrow-Derived Monocyte Chemoattractant Protein-1 Receptor CCR2 Is Critical in Angiotensin II-Induced Acceleration of Atherosclerosis and Aneurysm Formation in Hypercholesterolemic Mice
Arterioscler Thromb Vasc Biol, November 1, 2004; 24(11): e174 - e178.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Cell Physiol.Home page
R. Ginnan, P. J. Pfleiderer, K. Pumiglia, and H. A. Singer
PKC-{delta} and CaMKII-{delta}2 mediate ATP-dependent activation of ERK1/2 in vascular smooth muscle
Am J Physiol Cell Physiol, June 1, 2004; 286(6): C1281 - C1289.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
P. E. Szmitko, C.-H. Wang, R. D. Weisel, J. R. de Almeida, T. J. Anderson, and S. Verma
New Markers of Inflammation and Endothelial Cell Activation: Part I
Circulation, October 21, 2003; 108(16): 1917 - 1923.
[Full Text] [PDF]


Home page
SEMIN CARDIOTHORAC VASC ANESTHHome page
D. Striimper, M. Durieux, and P. Roekaerts
Endothelial and Microvascular Function
Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2003; 7(3): 225 - 238.
[Abstract] [PDF]


Home page
Exp. Biol. Med.Home page
S. Rattan, R. N. Puri, and Y.-P. Fan
Involvement of Rho and Rho-Associated Kinase in Sphincteric Smooth Muscle Contraction by Angiotensin II
Experimental Biology and Medicine, September 1, 2003; 228(8): 972 - 981.
[Abstract] [Full Text] [PDF]


Home page
Nephrol Dial TransplantHome page
L. A. Calo, E. Pagnin, P. A. Davis, M. Sartori, and A. Semplicini
Oxidative stress-related factors in Bartter's and Gitelman's syndromes: relevance for angiotensin II signalling
Nephrol. Dial. Transplant., August 1, 2003; 18(8): 1518 - 1525.
[Abstract] [Full Text] [PDF]


Home page
J. Clin. Endocrinol. Metab.Home page
K. Ino, C. Uehara, F. Kikkawa, H. Kajiyama, K. Shibata, T. Suzuki, E. E. Khin, M. Ito, M. Takeuchi, A. Itakura, et al.
Enhancement of Aminopeptidase A Expression during Angiotensin II-Induced Choriocarcinoma Cell Proliferation through AT1 Receptor Involving Protein Kinase C- and Mitogen-Activated Protein Kinase-Dependent Signaling Pathway
J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3973 - 3982.
[Abstract] [Full Text] [PDF]


Home page
HypertensionHome page
E. D. Motley, K. Eguchi, C. Gardner, A. L. Hicks, C. M. Reynolds, G. D. Frank, M. Mifune, M. Ohba, and S. Eguchi
Insulin-Induced Akt Activation Is Inhibited by Angiotensin II in the Vasculature Through Protein Kinase C-{alpha}
Hypertension, March 1, 2003; 41(3): 775 - 780.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
M. B. Taubman
Angiotensin II: A Vasoactive Hormone With Ever-Increasing Biological Roles
Circ. Res., January 10, 2003; 92(1): 9 - 11.
[Full Text] [PDF]


Home page
Circ. Res.Home page
A. H. Campos, Y. Zhao, M. J. Pollman, and G. H. Gibbons
DNA Microarray Profiling to Identify Angiotensin-Responsive Genes in Vascular Smooth Muscle Cells: Potential Mediators of Vascular Disease
Circ. Res., January 10, 2003; 92(1): 111 - 118.
[Abstract] [Full Text] [PDF]


Home page
J. Pharmacol. Exp. Ther.Home page
Z.-W. Hu, R. Kerb, X.-Y. Shi, T. Wei-Lavery, and B. B. Hoffman
Angiotensin II Increases Expression of Cyclooxygenase-2: Implications for the Function of Vascular Smooth Muscle Cells
J. Pharmacol. Exp. Ther., November 1, 2002; 303(2): 563 - 573.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
S. Kagiyama, S. Eguchi, G. D. Frank, T. Inagami, Y. C. Zhang, and M. I. Phillips
Angiotensin II-Induced Cardiac Hypertrophy and Hypertension Are Attenuated by Epidermal Growth Factor Receptor Antisense
Circulation, August 20, 2002; 106(8): 909 - 912.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
A. R. Brasier, A. Recinos III, and M. S. Eledrisi
Vascular Inflammation and the Renin-Angiotensin System
Arterioscler Thromb Vasc Biol, August 1, 2002; 22(8): 1257 - 1266.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
C. Mueller, S. Baudler, H. Welzel, M. Bohm, and G. Nickenig
Identification of a Novel Redox-Sensitive Gene, Id3, Which Mediates Angiotensin II-Induced Cell Growth
Circulation, May 21, 2002; 105(20): 2423 - 2428.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
C. Vickers, P. Hales, V. Kaushik, L. Dick, J. Gavin, J. Tang, K. Godbout, T. Parsons, E. Baronas, F. Hsieh, et al.
Hydrolysis of Biological Peptides by Human Angiotensin-converting Enzyme-related Carboxypeptidase
J. Biol. Chem., April 19, 2002; 277(17): 14838 - 14843.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
A. J. Edgley, N. R. Nichols, and W. P. Anderson
Acute intrarenal infusion of ANG II does not stimulate immediate early gene expression in the kidney
Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2002; 282(4): R1133 - R1139.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
P. Libby, P. M. Ridker, and A. Maseri
Inflammation and Atherosclerosis
Circulation, March 5, 2002; 105(9): 1135 - 1143.
[Abstract] [Full Text] [PDF]


Home page
Mol. Endocrinol.Home page
G. D. Frank, S. Saito, E. D. Motley, T. Sasaki, M. Ohba, T. Kuroki, T. Inagami, and S. Eguchi
Requirement of Ca2+ and PKC{delta} for Janus Kinase 2 Activation by Angiotensin II: Involvement of PYK2
Mol. Endocrinol., February 1, 2002; 16(2): 367 - 377.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
C. Berry, R. Touyz, A. F. Dominiczak, R. C. Webb, and D. G. Johns
Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide
Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2337 - H2365.
[Abstract] [Full Text] [PDF]


Home page
J. Am. Soc. Nephrol.Home page
M. FRANCO, E. TAPIA, J. SANTAMARIA, I. ZAFRA, R. GARCIA-TORRES, K. L. GORDON, H. PONS, B. RODRIGUEZ-ITURBE, R. J. JOHNSON, and J. HERRERA-ACOSTA
Renal Cortical Vasoconstriction Contributes to Development of Salt-Sensitive Hypertension after Angiotensin II Exposure
J. Am. Soc. Nephrol., November 1, 2001; 12(11): 2263 - 2271.
[Abstract] [Full Text] [PDF]


Home page
J. Pharmacol. Exp. Ther.Home page
J. Hines, J. N. Heerding, S. J. Fluharty, and D. K. Yee
Identification of Angiotensin II Type 2 (AT2) Receptor Domains Mediating High-Affinity CGP 42112A Binding and Receptor Activation
J. Pharmacol. Exp. Ther., August 1, 2001; 298(2): 665 - 673.
[Abstract] [Full Text] [PDF]


Home page
EndocrinologyHome page
A. Sugawara, K. Takeuchi, A. Uruno, Y. Ikeda, S. Arima, M. Kudo, K. Sato, Y. Taniyama, and S. Ito
Transcriptional Suppression of Type 1 Angiotensin II Receptor Gene Expression by Peroxisome Proliferator-Activated Receptor-{{gamma}} in Vascular Smooth Muscle Cells
Endocrinology, July 1, 2001; 142(7): 3125 - 3134.
[Abstract] [Full Text] [PDF]


Home page
Physiol. Rev.Home page
B. C. Berk
Vascular Smooth Muscle Growth: Autocrine Growth Mechanisms
Physiol Rev, July 1, 2001; 81(3): 999 - 1030.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
D. S. Weber and J. H. Lombard
Angiotensin II AT1 receptors preserve vasodilator reactivity in skeletal muscle resistance arteries
Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2196 - H2202.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
T. Omland, W. Johnson, M. B. Gordon, and M. A. Creager
Endothelial function during stimulation of renin-angiotensin system by low-sodium diet in humans
Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2248 - H2254.
[Abstract] [Full Text] [PDF]


Home page
HypertensionHome page
J.-H. Parmentier, M. M. Muthalif, A. T. Nishimoto, and K. U. Malik
20-Hydroxyeicosatetraenoic Acid Mediates Angiotensin II-Induced Phospholipase D Activation in Vascular Smooth Muscle Cells
Hypertension, February 1, 2001; 37(2): 623 - 629.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
D. Weiss, J. J. Kools, and W. R. Taylor
Angiotensin II-Induced Hypertension Accelerates the Development of Atherosclerosis in ApoE-Deficient Mice
Circulation, January 23, 2001; 103(3): 448 - 454.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
K. Arimura, K. Egashira, R. Nakamura, T. Ide, H. Tsutsui, H. Shimokawa, and A. Takeshita
Increased inactivation of nitric oxide is involved in coronary endothelial dysfunction in heart failure
Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H68 - H75.
[Abstract] [Full Text] [PDF]


Home page
Journal of Renin-Angiotensin-Aldosterone SystemHome page
N. Padmanabhan, S. Padmanabhan, and J. M. Connell
Genetic basis of cardiovascular disease -- the renin-angiotensin-aldosterone system as a paradigm
Journal of Renin-Angiotensin-Aldosterone System, December 1, 2000; 1(4): 316 - 324.
[PDF]


Home page
Pharmacol. Rev.Home page
R. M. Touyz and E. L. Schiffrin
Signal Transduction Mechanisms Mediating the Physiological and Pathophysiological Actions of Angiotensin II in Vascular Smooth Muscle Cells
Pharmacol. Rev., December 1, 2000; 52(4): 639 - 672.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
J. Jankowski, A. Schroter, M. Tepel, M. van der Giet, N. Stephan, J. Luo, W. Zidek, and H. Schluter
Isolation and Characterization of Coenzyme A Glutathione Disulfide as a Parathyroid-Derived Vasoconstrictive Factor
Circulation, November 14, 2000; 102(20): 2548 - 2552.
[Abstract] [Full Text] [PDF]


Home page
HypertensionHome page
M. M. Muthalif, N. A. Karzoun, L. Gaber, Z. Khandekar, I. F. Benter, A. E. Saeed, J.-H. Parmentier, A. Estes, and K. U. Malik
Angiotensin II-Induced Hypertension : Contribution of Ras GTPase/Mitogen-Activated Protein Kinase and Cytochrome P450 Metabolites
Hypertension, October 1, 2000; 36(4): 604 - 609.
[Abstract] [Full Text] [PDF]


Home page
EndocrinologyHome page
G. D. Frank, S. Eguchi, T. Yamakawa, S.-i. Tanaka, T. Inagami, and E. D. Motley
Involvement of Reactive Oxygen Species in the Activation of Tyrosine Kinase and Extracellular Signal-Regulated Kinase by Angiotensin II
Endocrinology, September 1, 2000; 141(9): 3120 - 3126.
[Abstract] [Full Text] [PDF]


Home page
Pharmacol. Rev.Home page
M. de Gasparo, K. J. Catt, T. Inagami, J. W. Wright, and Th. Unger
International Union of Pharmacology. XXIII. The Angiotensin II Receptors
Pharmacol. Rev., September 1, 2000; 52(3): 415 - 472.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
S. Meloche, J. Landry, J. Huot, F. Houle, F. Marceau, and E. Giasson
p38 MAP kinase pathway regulates angiotensin II-induced contraction of rat vascular smooth muscle
Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H741 - H751.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
M. Ruiz-Ortega, O. Lorenzo, M. Ruperez, S. Konig, B. Wittig, and J. Egido
Angiotensin II Activates Nuclear Transcription Factor {kappa}B Through AT1 and AT2 in Vascular Smooth Muscle Cells : Molecular Mechanisms
Circ. Res., June 23, 2000; 86(12): 1266 - 1272.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
J. Haendeler, M. Ishida, L. Hunyady, and B. C. Berk
The Third Cytoplasmic Loop of the Angiotensin II Type 1 Receptor Exerts Differential Effects on Extracellular Signal-Regulated Kinase (ERK1/ERK2) and Apoptosis via Ras- and Rap1-Dependent Pathways
Circ. Res., April 14, 2000; 86(7): 729 - 736.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
H. Tang, Z. J. Zhao, E. J. Landon, and T. Inagami
Regulation of Calcium-sensitive Tyrosine Kinase Pyk2 by Angiotensin II in Endothelial Cells. ROLES OF Yes TYROSINE KINASE AND TYROSINE PHOSPHATASE SHP-2
J. Biol. Chem., March 17, 2000; 275(12): 8389 - 8396.
[Abstract] [Full Text] [PDF]


Home page
Pharmacol. Rev.Home page
S. Kim and H. Iwao
Molecular and Cellular Mechanisms of Angiotensin II-Mediated Cardiovascular and Renal Diseases
Pharmacol. Rev., March 1, 2000; 52(1): 11 - 34.
[Abstract] [Full Text] [PDF]


Home page
Mol. Pharmacol.Home page
S. L. Grant, B. Lassègue, K. K. Griendling, M. Ushio-Fukai, P. R. Lyons, and R. W. Alexander
Specific Regulation of RGS2 Messenger RNA by Angiotensin II in Cultured Vascular Smooth Muscle Cells
Mol. Pharmacol., March 1, 2000; 57(3): 460 - 467.
[Abstract] [Full Text]


Home page
CirculationHome page
M. Usui, K. Egashira, H. Tomita, M. Koyanagi, M. Katoh, H. Shimokawa, M. Takeya, T. Yoshimura, K. Matsushima, and A. Takeshita
Important Role of Local Angiotensin II Activity Mediated via Type 1 Receptor in the Pathogenesis of Cardiovascular Inflammatory Changes Induced by Chronic Blockade of Nitric Oxide Synthesis in Rats
Circulation, January 25, 2000; 101(3): 305 - 310.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
S. Eguchi, H. Iwasaki, H. Ueno, G. D. Frank, E. D. Motley, K. Eguchi, F. Marumo, Y. Hirata, and T. Inagami
Intracellular Signaling of Angiotensin II-induced p70 S6 Kinase Phosphorylation at Ser411 in Vascular Smooth Muscle Cells. POSSIBLE REQUIREMENT OF EPIDERMAL GROWTH FACTOR RECEPTOR, RAS, EXTRACELLULAR SIGNAL-REGULATED KINASE, AND AKT
J. Biol. Chem., December 24, 1999; 274(52): 36843 - 36851.
[Abstract] [Full Text] [PDF]


Home page
HypertensionHome page
A. Hamaguchi, S. Kim, Y. Izumi, Y. Zhan, S. Yamanaka, and H. Iwao
Contribution of Extracellular Signal-Regulated Kinase to Angiotensin II–Induced Transforming Growth Factor-{beta}1 Expression in Vascular Smooth Muscle Cells
Hypertension, July 1, 1999; 34(1): 126 - 131.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
T. Takahashi, T. Taniguchi, H. Konishi, U. Kikkawa, Y. Ishikawa, and M. Yokoyama
Activation of Akt/protein kinase B after stimulation with angiotensin II in vascular smooth muscle cells
Am J Physiol Heart Circ Physiol, June 1, 1999; 276(6): H1927 - H1934.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
Y. Han, M. S. Runge, and A. R. Brasier
Angiotensin II Induces Interleukin-6 Transcription in Vascular Smooth Muscle Cells Through Pleiotropic Activation of Nuclear Factor-{kappa}B Transcription Factors
Circ. Res., April 2, 1999; 84(6): 695 - 703.
[Abstract] [Full Text] [PDF]


Home page
HypertensionHome page
S. Eguchi, H. Iwasaki, T. Inagami, K. Numaguchi, T. Yamakawa, E. D. Motley, K. M. Owada, F. Marumo, and Y. Hirata
Involvement of PYK2 in Angiotensin II Signaling of Vascular Smooth Muscle Cells
Hypertension, January 1, 1999; 33(1): 201 - 206.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
K. Tamura, N. Nyui, N. Tamura, T. Fujita, M. Kihara, Y. Toya, I. Takasaki, N. Takagi, M. Ishii, K.-i. Oda, et al.
Mechanism of Angiotensin II-mediated Regulation of Fibronectin Gene in Rat Vascular Smooth Muscle Cells
J. Biol. Chem., October 9, 1998; 273(41): 26487 - 26496.
[Abstract] [Full Text] [PDF]


Home page
J. Pharmacol. Exp. Ther.Home page
S. W. Watts, J. A. Florian, and K. M. Monroe
Dissociation of Angiotensin II-Stimulated Activation of Mitogen-Activated Protein Kinase Kinase from Vascular Contraction
J. Pharmacol. Exp. Ther., September 1, 1998; 286(3): 1431 - 1438.
[Abstract] [Full Text]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
H. Tomita, K. Egashira, M. Kubo-Inoue, M. Usui, M. Koyanagi, H. Shimokawa, M. Takeya, T. Yoshimura, and A. Takeshita
Inhibition of NO Synthesis Induces Inflammatory Changes and Monocyte Chemoattractant Protein-1 Expression in Rat Hearts and Vessels
Arterioscler Thromb Vasc Biol, September 1, 1998; 18(9): 1456 - 1464.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
S. Eguchi, K. Numaguchi, H. Iwasaki, T. Matsumoto, T. Yamakawa, H. Utsunomiya, E. D. Motley, H. Kawakatsu, K. M. Owada, Y. Hirata, et al.
Calcium-dependent Epidermal Growth Factor Receptor Transactivation Mediates the Angiotensin II-induced Mitogen-activated Protein Kinase Activation in Vascular Smooth Muscle Cells
J. Biol. Chem., April 10, 1998; 273(15): 8890 - 8896.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
B. Fisslthaler, V. B Schini-Kerth, I. Fleming, and R. Busse
Thrombin receptor expression is increased by angiotensin II in cultured and native vascular smooth muscle cells
Cardiovasc Res, April 1, 1998; 38(1): 263 - 271.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
S. Eguchi, P. J. Dempsey, G. D. Frank, E. D. Motley, and T. Inagami
Activation of MAPKs by Angiotensin II in Vascular Smooth Muscle Cells. METALLOPROTEASE-DEPENDENT EGF RECEPTOR ACTIVATION IS REQUIRED FOR ACTIVATION OF ERK AND p38 MAPK BUT NOT FOR JNK
J. Biol. Chem., March 9, 2001; 276(11): 7957 - 7962.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
S. Heeneman, J. Haendeler, Y. Saito, M. Ishida, and B. C. Berk
Angiotensin II Induces Transactivation of Two Different Populations of the Platelet-derived Growth Factor beta Receptor. KEY ROLE FOR THE p66 ADAPTOR PROTEIN Shc
J. Biol. Chem., May 19, 2000; 275(21): 15926 - 15932.
[Abstract] [Full Text] [PDF]


This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Griendling, K. K.
Right arrow Articles by Alexander, R. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Griendling, K. K.
Right arrow Articles by Alexander, R. W.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*L-TYROSINE