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(Hypertension. 1998;32:338-345.)
© 1998 American Heart Association, Inc.

Third Workshop on Structure and Function of Large Arteries: Part II

Signal Transduction of Mechanical Stresses in the Vascular Wall

Stéphanie Lehoux; ; Alain Tedgui

From INSERM U141, Paris, France.

Correspondence to Alain Tedgui, INSERM U141, 41 Blvd de la Chapelle, 75475 Paris, Cedex 10, France. E-mail tedgui{at}infobiogen.fr

Abstract

Abstract—The vascular wall is constantly subjected to a variety of mechanical forces in the form of stretch (tensile stress), due to blood pressure, and shear stress, due to blood flow. Alterations in either of these stresses are known to result in vascular remodeling, an adaptation characterized by modified morphology and function of the blood vessels, allowing the vessels to cope with physiological or pathological conditions. The processes involved in vascular remodeling include cellular hypertrophy and hyperplasia, as well as enhanced protein synthesis or extracellular matrix protein reorganization. In vitro studies using vascular cells have attempted to identify the mechanisms behind structural alterations. Possible pathways include ion channels, integrin interaction between cells and the extracellular matrix, activation of various tyrosine kinases (such as c-Src, focal adhesion kinase, and mitogen-activated protein kinases), and autocrine production and release of growth factors. These pathways lie upstream of de novo synthesis of immediate response genes and total protein synthesis, both of which are likely to be involved in the process of vascular remodeling.

Key Words: shear stress • stretch • muscle, smooth • endothelium • MAP kinases

Blood vessels are permanently subjected to mechanical forces in the form of stretch, which because of the pulsatile nature of blood flow exposes vessels to cyclic mechanical strain, and shear stress. Blood pressure is the major determinant of vessel stretch. It creates radial and tangential forces that counteract the effects of intraluminal pressure and that affect all cell types in the vessel. In comparison, fluid shear stress results from the friction of blood against the vessel wall, and it acts in parallel to the vessel surface. Accordingly, shear is sensed principally by endothelial cells, strategically located at the interface between the blood and the vessel wall. Alterations in stretch or shear stress invariably produce transformations in the vessel wall that will aim to accommodate the new conditions and ultimately restore basal levels of tensile stress and shear stress.^{1 2 3} Hence, while acute changes in stretch or shear stress correlate with transient adjustments in vessel diameter, mediated through release of vasoactive agonists or change in myogenic tone, chronically altered mechanical forces usually instigate important adaptive alterations of vessel wall shape and composition. The concept of vascular remodeling has therefore been used to describe the transformations that occur in vessels undergoing mechanical stresses. For example, experimental hypertension is accompanied by increased wall thickness, resulting in resistance arteries and arterioles from VSMC hyperplasia and in conductance arteries from hypertrophy.^{4 5} Likewise, reduced mechanical strain translates into vessel atrophy.

Several reports describe the effects of mechanical stretch on hypertrophy of the heart, and the pathways leading to these events have been studied extensively in cardiac cells (reviewed in Reference 6⁶ ). More recently, investigators have identified how mechanical forces are sensed and transduced into biochemical signals by multiple pathways within the vascular cells, resulting in various biological responses. Located at the cell surface, integrins are likely to be key mechanosensors. In parallel, ion channels and other unknown stretch receptors presumably transduce the mechanical signal. As a result, several intracellular signaling pathways are activated, including the FAK pathway, the MAP kinase cascade, and the renin-angiotensin system (Figure 1).

View larger version (44K): [in this window] [in a new window]   Figure 1. Multiple pathways of transduction of mechanical stretch in vascular cells. Mechanical forces may act on /ß heterodimer integrins and could activate nonreceptor membrane tyrosine kinases including c-Src*. Activated c-Src* may stimulate FAK autophosphorylation, allowing association of the Shc-Grb2-Sos complex and downstream activation of MAP kinase. MAP kinase may simulate growth or protein synthesis via activation of S6 kinase (S6K). Alternatively, stretch acts on unknown stretch receptors (STR) that stimulate the renin-angiotensin system, leading to the production of Ang II (AII), which in turn acts on G-protein coupled receptors. Autocrine production of growth factors including PDGF may activate tyrosine kinase receptors (R TyK).

Mechanical Forces and Vascular Cell Phenotype

Effects of Stretch
Mechanical stretching of VSMCs produces a variety of responses that account for vessel morphology. On one hand, stretch may be at the very core of the VSMC differentiated state. Indeed, in a model of cultured rabbit aorta, we determined that a certain level of stretch is crucial for the maintenance of the differentiated phenotype of the VSMC. Vessels placed in conditions of abnormally low intraluminal pressure (10 mm Hg) showed decreased content, over 3 to 6 days, of smooth muscle marker proteins h-caldesmon and filamin despite the presence of fetal calf serum, a known mitogen, in the culture medium. In comparison, loss of these proteins was prevented in aortic segments kept at physiological intraluminal pressure (80 mm Hg).⁷ The presence of endothelium was not essential for maintenance of VSMC marker proteins. These results corroborate earlier experiments, in which cyclic stretching of cultured VSMCs was shown to increase (or rather prevent the decrease of) the expression of smooth muscle myosin heavy chains and myosin light chain kinase.⁸ Furthermore, cyclic stretching (12 to 72 hours) of VSMCs augmented smooth muscle myosin heavy chain SM-1 and SM-2 protein content and decreased nonmuscle myosin-A compared with static VSMC cultures.⁹ Because only SM-1 showed enhanced mRNA expression under cyclic strain,⁹ the relative increase in SM-2 was presumably due to reduced degradation of this marker protein. Therefore, constant mechanical stimulation appears to be required for maintenance of normal contractile phenotype of VSMCs in the arterial wall. Loss of stretch, together with loss of ECM contacts, is probably a major cause of differentiation of VSMCs in culture. However, while a certain level of stretch is required to maintain VSMCs in a quiescent state, overstretching triggers adaptive processes that result in increased protein synthesis and hypertrophy.

In fact, organ culture of aortas maintained during 3 to 6 days at high intraluminal pressure (150 mm Hg) revealed that both total protein synthesis and fibronectin content are enhanced by stretch.¹⁰ Interestingly, DNA synthesis remains unchanged in the same preparations, in keeping with observations of pressure-induced hypertrophy but not hyperploidy in large vessels in vivo⁴ and contrary to DNA synthesis induction by stretch in VSMC culture.^{11 12} In the latter case, absence of interaction with the ECM environment is certainly responsible for the hyperplasic response to stretch.

Effects of Shear
The fact that shear acts mainly on endothelial cells, while stretch has repercussions on the entire vessel wall, does not rule out the likelihood that long-term changes in blood flow will bring about vascular remodeling, characterized by altered vessel wall thickness, matrix composition, and wall organization.¹³ Accordingly, in endothelial cells subjected to oscillatory flow, fibronectin and laminin content was found to be greater than that in static cultures.¹⁴ However, although laminar shear stress may lead to a reorganization of cytoskeletal proteins and change of cell shape, it apparently does not change protein levels in cultured endothelial cells.¹⁵ On the other hand, a variety of genes encoding for growth factors (PDGF, transforming growth factor),^{16 17} vasodilators (NO, prostacyclin),^{3 18 19 20} vasoconstrictors (endothelin),²¹ and adhesion molecules (intercellular adhesion molecule)²² are regulated on shear stimulation. While a number of these inductions are transient, some persist and may mediate long-term alterations in vessel structure and function that occur through regulation of protein and gene expression.³ Finally, pressure-induced circumferential cyclic strain increases endothelial cell sensitivity to shear stress, resulting in a lowered threshold level of shear to provoke structural responses.²³ Ultimately, concomitant stimulation of vascular cells by both stretch and shear stress may produce maximal remodeling responses in the vessel.

Transmission of Mechanical Stresses at the Cell Membrane

Integrins
Strategically situated at the boundary between the ECM and the cytoskeleton, integrins may act not only as mediators of cell adhesion but they can also transduce biochemical signals across the cell membrane. Indeed, integrins are present at sites of close apposition of the cell surface and the ECM, and they form a bridge between matrix proteins and the cytoskeleton, mediating binding and attachment of the cell to components of the ECM (such as fibronectin, vitronectin, and collagen) and creating focal adhesions.^{24 25} A role for integrins as mediators of vascular strain is supported by observations that shear stress–induced tyrosine phosphorylation of endothelial cells in isolated arterioles exposed to intraluminal flow is abolished by inhibition of integrin binding to ECM proteins containing the RGD amino acid sequence,²⁶ RGD being the key combination via which ECM proteins are bound by integrins. Response to strain is also abrogated by antibodies to ß3 or vß5 integrins, which bind fibronectin,¹² whereas flow-dependent vasodilation is RGD- and ß3 integrin–sensitive²⁶ and is blocked by removal of the glycocalyx with neuraminidase.²⁷ ß3 Integrin expression may actually be enhanced subsequent to cyclic stretching of endothelial cells.²⁸ In addition, mechanical strain of VSMCs grown on fibronectin or vitronectin induces cell proliferation, whereas elastin- or laminin-grown cells in the same conditions do not proliferate.¹² On the other hand, neonatal VSMCs grown on laminin express SM-1 and SM-2 smooth muscle myosin heavy chains in response to mechanical strain, unlike cells grown on the poly RGD substrate pronectin,²⁹ and cyclic stretch–induced SM-1 expression is greater in cells grown on laminin than on collagen or fibronectin.⁹ It therefore appears that both the ability of cells to sense mechanical strain and the ensuing biochemical response depend on the nature of the interaction of specific integrins with the ECM. Ultimately, the hyperplasic versus hypertrophic response to stretch of VSMCs exposed to ECM will depend on their phenotype, as suggested by organ culture experiments in which stretch produces matrix synthesis without inducing cell proliferation.¹⁰

A recent report brings evidence that some ECM proteins actually serve as ligands to receptors. This is true at least in the case of collagen, which binds and activates the receptor-like tyrosine kinase discoidin domain receptor 1 (DDR1), a first example of a ligand shared by integrins and receptor tyrosine kinases. In this case, the receptors are phosphorylated with a protracted time course.³⁰ Collagen might thus signal via its 2 distinct receptor classes to regulate cellular responses to changes in the surrounding environment.³⁰ Hence, integrin-mediated cell signaling could implicate either a cytoskeletal alteration removing a constraint on the signal transduction machinery, or a direct action on the signaling systems, or a combination of both.³¹

Ion Channels
Submitting endothelial cells to either shear stress or stretch spurs a transient increase in intracellular calcium and divalent cations.^{32 33} Endothelial cells possess stretch-activated ion channels that are relatively nonselective across cations.³⁴ These were identified using patch-clamp techniques. In isolated endothelial cells, membrane stretching by applying suction through the patch electrode increased the opening frequency of channels permeable to calcium.³⁵ Mechanosensitive ion channels were further characterized by their sensitivity to gadolinium but not to classic calcium channel blockers such as nifedipine.³³ The presence of mechanotransducing ion channels in endothelial cells may help explain how the endothelium mediates vascular responses to hemodynamic stresses. For example, the mechanism of stretch-activated phospholipase C activity in VSMCs was found to involve influx of calcium via gadolinium-sensitive ion channels but not via nifedipine-sensitive ion channels.³⁶ MAP kinase activation by Ang II also shows a calcium dependency in VSMCs.³⁷ On the other hand, potassium channels distinct from the nonselective gadolinium-sensitive cation channels may also participate in transduction of mechanical stress.³⁸ This was demonstrated by the observation that shear-induced increases in gene expression and cGMP concentrations are inhibited by tetraethylammonium ion, a nonspecific potassium channel blocker.³⁹ Furthermore, membrane stretch and fatty acids directly activate large conductance calcium-activated potassium channels in VSMCs.⁴⁰ Finally, RSK, a downstream target of ERK1/2, phosphorylates or may actually itself be the NHE-1 isoform of the Na⁺-H⁺ exchanger.⁴¹ This is particularly interesting in light of the observation that cellular sodium entry via a tetrodotoxin-inhibited mechanosensitive channel modulates ERK1/2 activation by shear.⁴² Either way, there appears to be a definite role for ion channels in the response of vascular cells to mechanical forces.

Intracellular Transmission of Mechanical Stresses

Focal Adhesion Kinases
At the cellular level, subjecting endothelial cells to oscillatory flow spurs a clustering of 5ß1 integrins and a concomitant gathering of the cytoskeletal proteins talin and vinculin.¹⁴ In fact, during cell stimulation by mechanical factors such as stretch or shear stress, several signaling events are associated with the formation of focal adhesions, which consist of clustered integrins and accumulated cytoskeletal proteins. The recruitment of integrins into focal adhesions is mediated by the cytoplasmic domains of the bridging proteins, as deletion of the ß1 subunit cytoplasmic domain inhibits integrin association.⁴³ In turn, the cytoplasmic domains bind cellular cytoskeletal proteins that are present in the focal adhesions -actinin and talin.^{44 45} -Actinin is directly connected to actin microfilaments,⁴⁶ whereas talin is linked via vinculin,⁴⁷ which in turn binds -actinin or tensin,⁴⁸ both of which associate with actin.⁴⁹

Proteins present at focal adhesions, in particular the 125-kDa cytoplasmic tyrosine kinase FAK, become tyrosine phosphorylated when cells are stimulated by integrin antibodies, cell adhesion, or RGD-containing compounds.^{50 51 52} Shear and adhesion activate FAK, but stimuli are not additive.^{53 54 55} FAK associates with paxillin⁵⁶ and talin,⁵⁷ and both FAK and paxillin can bind to the cytoplasmic tail of integrins independently.⁵⁸ Focal adhesions containing talin, vinculin, and paxillin have been reported to form in endothelial cells despite the absence of FAK association and in conditions of reduced tyrosine phosphorylation; these findings suggest that FAK activation is downstream of focal adhesion and stress fiber formation and that its role is one of a signaling protein in focal adhesions rather than of focal adhesion assembly.⁵⁹ In confirmation, there is evidence that aggregation of FAK with 5ß1 integrin, RGD, or fibronectin occurs even in the presence of tyrosine kinase inhibition or actin filament assembly disruption by cytochalasin D. However, cytoskeletal protein recruitment and activation of downstream kinases is prevented.^{60 61} Rho, a small G protein, is also implicated in the regulation of formation of stress fibers and focal adhesions, through phosphorylation of FAK, p130Cas (an adaptor protein bound by FAK), and paxillin, and, independently, actin polymerization.⁶² FAK may be downstream of Rho, and Rho may be involved in activation of FAK by 7 transmembrane domain receptors of Ang II, bombesin, and lysophosphatidic acid.³¹

Shear in endothelial cells increases the tyrosine phosphorylation and activity of FAK and its association with Grb2.⁵³ In fact, it is the attachment of c-Src, a membrane-associated nonreceptor tyrosine kinase, at a key region of autophosphorylation on FAK that creates a binding site for the Src-homology-2 (SH2) domain of Grb2.⁶³ C-Src is active in its dephosphorylated state, which seems to be modulated by stretch,⁶⁴ and is inactivated by C-terminal Src kinase (Csk). After its activation, c-Src is translocated to focal contacts (Figure 2).

View larger version (30K): [in this window] [in a new window]   Figure 2. Schematic representation of c-Src activation by stretch. Once stimulated, activated c-Src (c-Src*) translocates to focal contacts where it interacts with FAK. C-Src is phosphorylated, and therefore returned to its inactive state, via the action of C-terminal Src kinase (Csk).

MAP Kinase Cascade: Upstream Events
The MAP kinase cascade is a major pathway through which signals coming from growth factors and mechanical strain are transduced into regulation of gene expression and protein synthesis. Involved are the sequential phosphorylation and activation of the cytoplasmic protein kinases MEKK, MEK, and finally MAP kinase.⁶⁵ The MAP kinase cascade actually comprises 3 separate pathways that respond to different stimuli and instigate distinct cellular responses. Phosphorylation of 1 MAP kinase, which lies downstream of the MEKK Raf and is present in 2 isoforms termed ERK 1 and 2, leads to the activation of regulatory proteins both in the cytoplasm and the nucleus.⁶⁵ A second branch of the MAP kinase family, termed stress-activated protein kinases (SAPK) because they are activated by such stimuli as UV light, heat shock, hypoxia, or high osmolarity, includes kinases that phosphorylate the amino terminal of transcription factor c-jun (JNK).^{66 67} Finally, a third branch of the MAP kinase family comprises p38, also activated by osmotic stress.⁶⁸ In endothelial cells, physiological levels of shear stimulate ERK1/2,^{54 69 70} whereas cyclic mechanical strain activates both ERK1/2 and JNK in VSMCs.²⁹ Furthermore, applying a high intraluminal pressure to aortas in organic culture induces a biphasic ERK1/2 stimulation, characterized by an acute peak in activity, subsequent reversal, and a second more lengthy activation⁷¹ (Figure 3). In vivo, ERK1/2 is transiently activated by acute hypertension⁷² and by vessel wall injury with a balloon catheter.^{73 74}

View larger version (28K): [in this window] [in a new window]   Figure 3. Time course of ERK1/2 activation in aortic organ culture by intraluminal pressure. Rabbit aortic segments were pressurized at 150 mm Hg during different times. A, Autoradiogram of in-gel kinase assays of ERK1 and ERK2 activity using myelin basic protein as the substrate. B, Quantification of in-gel assays. *P<0.05; **P<0.01 vs 0 minutes. Modified from Birukov et al.71

Diverse pathways link mechanical strain to MAP kinase activation in vascular cells. Hence, G-protein and calcium-independent PKC activation is involved in ERK1/2 activation by shear stress,⁷⁰ whereas in certain conditions JNK may be more activated by shear than ERK1/2, through sequential phosphorylation of Sos, Ras, and MEKK.⁶⁹ Furthermore, integrins are likely to be among the actors involved in the transmission of mechanical forces to the MAP kinase cascade, for several reasons. First, cellular response to stretch or shear stress in vitro varies widely depending on the nature of the substrate on which the cells are grown. For example, ERK1/2 and JNK are both activated by cyclic mechanical strain in pronectin-grown neonatal VSMCs, whereas in their laminin-grown counterparts, only JNK is stimulated by cyclic strain.²⁹ Second, ERK1/2 activation by shear stress and by integrin-mediated adhesion to fibronectin occurs via a common herbimycin A–sensitive, PKC-dependent pathway in endothelial cells.⁵⁴

Src-family tyrosine kinases, which are inhibited by herbimycin A, have also been implicated in intraluminal pressure–induced ERK1/2 activation in vascular organ culture, although a PKC-independent pathway was involved under these conditions.⁷¹ Recent in vitro experiments report a role for c-Src in pressure-induced contraction of rat cerebral arteries.⁷⁵ Furthermore, both c-Src and Grb2 SH2 binding motifs have been involved in MAP kinase signaling pathways.⁶³ Accordingly, it was demonstrated that FAK overexpression enhances c-Src kinase activity and fibronectin-induced ERK2 activity, whereas a Ras dominant negative, which blocked ERK activation, did not affect FAK phosphorylation or Src activity. Also, replacing the c-Src binding site on FAK prevented integrin signaling to ERK.⁶³ Finally, fibronectin-induced ERK1/2 activation is Shc-dependent, and the Shc-ERK pathway is bridged by Ras.⁷⁶ Hence, these cumulative observations describe a pathway originating with integrin activation, focal adhesion assembly, activation of FAK by c-Src, association with Grb2 leading to Shc-dependent stimulation of Ras, and subsequent activation of ERK1/2 via the MAP kinase cascade (Figure 1). Accordingly, a dominant negative mutant of FAK was shown to attenuate shear-induced ERK2 and JNK activity in endothelial cells, as did a dominant negative mutant of Sos and an anti-vitronectin receptor antibody.⁵³ Likewise, both flow and ß1-integrin activation stimulated ERK1/2 and tyrosine phosphorylation of proteins. However, ERK1/2 activation by ß1-integrin activation occurred more slowly and to a lesser degree, and fewer proteins were tyrosine phosphorylated, than under flow conditions.⁵⁵ Multiple pathways are then likely to be recruited in the mechanotransduction of flow.

There is indeed evidence that integrin-mediated MAP kinase activation may in some cases bypass FAK, as demonstrated by the observation that a single-chain tailless mutant of integrin 1 recruited Shc and activated ERK but not FAK, whereas an activating 6ß1 antibody activated FAK but did not induce its association with Shc and did not activate ERK.⁷⁶ Furthermore, the increase in adhesion-mediated ERK activation by shear was only partially affected by actin filament disruption,⁵⁴ and JNK, but not ERK, remains activated by fibronectin despite the presence of cytochalasin D.⁶¹

MAP Kinase Cascade: Downstream Events
Events downstream to MAP kinase activation are numerous and varied. Once phosphorylated, ERK1/2 may translocate to the nucleus to phosphorylate transcription factors and thereby regulate cell cycle gene expression.⁷⁷ Both ERK1/2 and JNK can lead to ternary complex formation at the serum response element, present on several gene promoters, and to increased transcriptional activity.⁷⁸ Alternatively, phosphorylation of the translation regulator protein PHAS-I (phosphorylated heat- and acid-stable protein) promotes the dissociation of the PHAS-I–eukaryotic initiation factor (eIF) 4E complex, normally tightly bound when PHAS-I is relatively underphosphorylated, releasing eIF-4E that will facilitate initiation of translation in the nucleus.^{79 80} Another downstream target of ERK in VSMCs is the 90-kDa ribosomal S6 kinase RSK, which through activation of the transfer RNA-binding factor may provide a pathway essential for the initiation of translation.⁸⁰ Ultimately, ERK1/2 activation coincides with enhanced c-fos and c-jun expression, and activation of the AP-1 transcription factor,⁷² and it is likely to play a significant role in regulating cell cycle progression of VSMCs⁸¹ as well as protein synthesis.⁸⁰

The fact that ERK1/2 can also induce cyclooxygenase-2 in VSMCs⁸² may explain why activation of this MAP kinase does not necessarily result in increased cellular proliferation. Indeed, cytosolic phospholipase A₂ is among the substrates of ERK1/2.⁸³ Phospholipase A₂ catalyzes the release of arachidonic acid from phospholipids in the cell membrane,⁸⁴ which will be transformed by the action of cyclooxygenase-2 into prostaglandins. The resulting elevated levels of prostaglandin E₂ and protein kinase A activation could counteract ERK1/2-induced proliferation.⁸² A further target of activated ERK1/2 has been reported to be the contractile regulatory protein h-caldesmon, the high-molecular-weight form of caldesmon, indicating that ERK is involved in the regulation of contractile properties of the vascular wall.⁸⁵ Hence, in the end, the availability of downstream ligands may be a significant determinant of the biological outcome of ERK activation.⁸² At length, ERK1/2 activity is modulated by MAP kinase phosphatase (MKP-1), which dephosphorylates the enzyme.⁸⁶ Alternatively, the activation of ERK1/2 may be terminated through a feedback loop, implicating Ras/Raf-mediated suppression of integrin activation.⁸⁷

Role of the Renin-Angiotensin System and Growth Factors

Induction of protein synthesis by stretch may occur in many cases via increased synthesis of growth factors or mitogenic agonists, among which Ang II plays an important role. The pathways involved in the increased synthesis of these factors by mechanical strain are not yet clearly understood, although there is evidence that the AP-1 transcription factor downstream of ERK1/2 activation may regulate growth factor expression.⁸⁸ Stimulation of protein and fibronectin synthesis by high intraluminal pressure in aortic organ culture was found not only to result from augmented angiotensin levels but also to be further enhanced by addition of Ang II to the culture medium.¹⁰ In a similar fashion, the rise in transforming growth factor-ß mRNA expression brought about by Ang II and stretch is additive,⁸⁹ stretch induces parathyroid hormone–related peptide mRNA and secretion synergistically with Ang II,⁹⁰ and both stretch- and Ang II–induced DNA synthesis in collagen-plated VSMCs occurs in synergy.¹¹ Moreover, this latter effect is attenuated by PDGF antibodies (PDGF-AB), whereas Ang II and PDGF increase DNA synthesis in synergy,¹¹ demonstrating that more than 1 factor at once may be implicated in the remodeling process. In addition, a role for ECM proteins cannot be excluded. Indeed, attachment of cells to fibronectin and antibody-induced aggregation of 5ß1 integrins enhances PDGF-induced increase in cytoplasmic pH,³² suggesting that integrins and growth factor receptors may act cooperatively.

In several circumstances, mechanical activation of vessels or vascular cells instigates the release of vasoactive factors that will be implicated in the ensuing changes in vessel structure and function. In organ culture, for example, angiotensin mediates the enhanced total protein and fibronectin synthesis induced by high intraluminal pressure.⁹¹ Appropriately, Ang II is potentially involved in the stimulation of a number of intracellular pathways, leading in aortic VSMCs to hypertrophy, through enhanced protein synthesis, but not to hyperploidy.^{10 92} Synthesis-promoting activities of Ang II are transduced via the angiotensin II subtype 1 receptor,⁹¹ and the downstream signaling cascades include activation of phospholipases C and D, increased calcium, and inhibition of adenylyl cyclase.^{93 94} Ang II may also induce protein synthesis, in part via activation of the 70-kDa S6 kinase, by an ERK1/2-independent pathway.⁹⁵ This is particularly interesting in light of the fact that intraluminal pressure induces both ERK1/2 activation and protein synthesis, but only the latter effect is mediated by Ang II.^{10 71} Alternatively, Ang II activates c-Src,⁹⁶ which constitutes a probable pathway by which Ang II phosphorylates both FAK and paxillin.⁹³ In fact, not only Ang II but also epidermal growth factor and thrombin activate tyrosine phosphorylation of paxillin, as demonstrated in rat aortic VSMCs.⁹³ Not surprisingly, growth factors (fibroblast growth factor, PDGF-BB, epidermal growth factor) and integrins can activate the MAP kinase cascade in synergy, provided the integrins are both aggregated and occupied.⁹⁷ Like Ang II, growth factors (insulin) may activate relatively downstream events in the signaling cascade, such as 70-kDa S6 kinase stimulation and phosphorylation of PHAS-I, via MAP kinase–independent pathways.⁷⁹

Growth factors may bypass the MAP kinase cascade and function instead by activating NFB.⁹⁸ This family of transcription factors regulates the expression of genes encoding growth factors, inducible surface proteins, and molecules involved in ECM remodeling.⁹⁹ NFB is present in the cytosol in association with 1 of several inhibitors (generally identified as IB), forming an inactive heteromeric complex. NFB is released after phosphorylation and subsequent degradation of the IB, allowing the active NFB dimers to translocate to the nucleus and promote transactivation of target genes.^{57 100}

In parallel, recent reports propose a role for reactive oxygenated species in mechanical stress signal transduction. Indeed, stretch of VSMCs activates PKC, which presumably acts on NADPH oxidase, and thereby forms reactive oxygen species that then sequentially activate NFB and DNA synthesis.¹⁰¹ Alternatively, H₂O₂ in endothelial cells also induces f-actin reorganization, characterized by stress fiber formation and recruitment of vinculin to focal adhesions. These changes are modulated by activation of p38, followed by phosphorylation of heat shock protein HSP27.¹⁰² Furthermore, observations of shear stress–induced oxygen free radical production and downstream HSP27 activation are combined in a single study describing sustained phosphorylation of HSP27 in endothelial cells subjected to shear stress and consequent reorganization of cytoskeletal proteins and change of cell shape.¹⁵ Finally, a recent study identified 2 members of the MAD protein family (for mothers against decapentaplegic), Smad6 and Smad7, as unique among the MAD-related proteins, being expressed selectively in the endothelium in vivo and activated by physiological levels of flow in endothelial cell cultures.¹⁰³ MAD proteins traditionally act as second messengers distal to the transforming growth factor-ß family of receptors.¹⁰³

Conclusion

Understanding which signaling pathways are involved in the transduction of mechanical forces in the vascular wall should allow for a better approach to vascular remodeling. This may be of help in the development of novel therapeutic strategies for the treatment of cardiovascular diseases, including hypertension, atherosclerosis, and restenosis after angioplasty.

Selected Abbreviations and Acronyms

Ang II = angiotensin II ECM = extracellular matrix ERK = extracellular signal–related kinase FAK = focal adhesion kinase MAP = mitogen-activated protein MEK = MAP kinase kinase MEKK = MAP kinase kinase kinase NFB = nuclear factor-B PDGF = platelet-derived growth factor PKC = protein kinase C VSMC = vascular smooth muscle cell

Received January 24, 1998; first decision February 11, 1998; accepted April 13, 1998.

References

1. Glagov S. Intimal hyperplasia, vascular remodeling, and the restenosis problem. Circulation. 1994;89:2888–2891.[Free Full Text]

2. Barbee KA, Macarak EJ, Thibault LE. Strain measurements in cultured vascular smooth muscle cells subjected to mechanical deformation. Ann Biomed Eng. 1994;22:14–22.[Medline] [Order article via Infotrieve]

3. Tronc F, Wassef M, Esposito B, Henrion D, Glagov S, Tedgui A. Role of NO in flow-induced remodeling of the rabbit common carotid artery. Arterioscler Thromb Vasc Biol. 1996;16:1256–1262.[Abstract/Free Full Text]

4. Wolinsky H. Response of the rat aortic media to hypertension: morphological and chemical studies. Circ Res. 1970;26:507–522.[Abstract/Free Full Text]

5. Owens GK, Schwartz SM, McCanna M. Evaluation of medial hypertrophy in resistance vessels of spontaneously hypertensive rats. Hypertension. 1988;11:198–207.[Abstract/Free Full Text]

6. Sadoshima J, Izumo S. The cellular and molecular response of cardiac myocytes to mechanical stress. Annu Rev Physiol. 1997;59:551–571.[Medline] [Order article via Infotrieve]

7. Birukov KG, Bardy N, Lehoux S, Merval R, Shirinsky VP, Tedgui A. Intraluminal pressure is essential for the maintenance of smooth muscle caldesmon and filamin content in aortic organ culture. Arterioscler Thromb Vasc Biol. 1998;18:922–927.[Abstract/Free Full Text]

8. Smith PG, Tokui T, Ikebe M. Mechanical strain increases contractile enzyme activity in cultured airway smooth muscle cells. Am J Physiol. 1995;268:L999–L1005.[Abstract/Free Full Text]

9. Reusch P, Wagdy H, Reusch R, Wilson E, Ives HE. Mechanical strain increases smooth muscle and decreases nonmuscle myosin expression in rat vascular smooth muscle cells. Circ Res. 1996;79:1046–1053.[Abstract/Free Full Text]

10. Bardy N, Karillon GJ, Merval R, Samuel J-L, Tedgui A. Differential effects of pressure and flow on DNA and protein synthesis, and on fibronectin expression by arteries in a novel organ culture system. Circ Res. 1995;77:684–694.[Abstract/Free Full Text]

11. Sudhir K, Wilson E, Chatterjee K, Ives HE. Mechanical strain and collagen potentiate mitogenic activity of angiotensin-II in rat vascular smooth muscle cells. J Clin Invest. 1993;92:3003–3007.

12. Wilson E, Sudhir K, Ives HE. Mechanical strain of rat vascular smooth muscle cells is sensed by specific extracellular matrix/integrin interactions. J Clin Invest. 1995;96:2364–2372.

13. Davies PF. Flow-mediated endothelial mechanotransduction. Physiol Rev. 1995;75:519–560.[Abstract/Free Full Text]

14. Thoumine O, Nerem RM, Girard PR. Oscillatory shear stress and hydrostatic pressure modulate cell-matrix attachment proteins in cultured endothelial cells. In Vitro Cell Dev Biol Animal. 1995;31:45–54.[Medline] [Order article via Infotrieve]

15. Li S, Piotrowicz RS, Levin EG, Shyy YJ, Chien S. Fluid shear stress induces the phosphorylation of small heat shock proteins in vascular endothelial cells. Am J Physiol. 1996;40:C994–C1000.

16. Malek AM, Gibbons GH, Dzau VJ, Izumo S. Fluid shear stress differentially modulates expression of genes encoding basic fibroblast growth factor and platelet-derived growth factor-B chain in vascular endothelium. J Clin Invest. 1993;92:2013–2021.

17. Hsieh HJ, Li NQ, Frangos JA. Shear stress increases endothelial platelet-derived growth factor messenger RNA levels. Am J Physiol. 1991;260:H642–H646.[Abstract/Free Full Text]

18. Furchgott RF, Vanhoutte PM. Endothelium-derived relaxing and contracting factors. FASEB J. 1989;3:2007–2018.[Abstract]

19. Bhagyalakshmi A, Frangos JA. Mechanism of shear-induced prostacyclin production in endothelial cells. Biochem Biophys Res Commun. 1989;158:31–37.[Medline] [Order article via Infotrieve]

20. Nadaud S, Philippe M, Arnal JF, Michel JB, Soubrier F. Sustained increase in aortic endothelial nitric oxide synthase expression in vivo in a model of chronic high blood flow. Circ Res. 1996;79:857–863.[Abstract/Free Full Text]

21. Kuchan MJ, Frangos JA. Shear stress regulates endothelin-1 release via protein kinase C and cGMP in cultured endothelial cells. Am J Physiol. 1993;264:H150–H156.[Abstract/Free Full Text]

22. Golledge J, Turner RJ, Harley SL, Springall DR, Powell JT. Circumferential deformation and shear stress induce differential responses in saphenous vein endothelium exposed to arterial flow. J Clin Invest. 1997;99:2719–2726.[Medline] [Order article via Infotrieve]

23. Zhao SM, Suciu A, Ziegler T, Moore JE, Burki E, Meister JJ, Brunner HR. Synergistic effects of fluid shear stress and cyclic circumferential stretch on vascular endothelial cell morphology and cytoskeleton. Arterioscler Thromb Vasc Biol. 1995;15:1781–1786.[Abstract/Free Full Text]

24. Burridge K, Fath K, Kelly T, Nuckolls G, Turner C. Focal adhesions: transmembrane junctions between the extracellular matrix and the cytoskeleton. Annu Rev Cell Biol. 1988;4:487–525.

25. Haas TA, Plow EF. Integrin-ligand interactions: a year in review. Curr Opin Cell Biol. 1994;6:656–662.[Medline] [Order article via Infotrieve]

26. Muller JM, Chilian WM, Davis MJ. Integrin signaling transduces shear stress–dependent vasodilation of coronary arterioles. Circ Res. 1997;80:320–326.[Abstract/Free Full Text]

27. Hecker M, Mulsch A, Bassenge E, Busse R. Vasoconstriction and increased flow: two principal mechanisms of shear stress-dependent endothelial autacoid release. Am J Physiol. 1993;265:H828–H833.[Abstract/Free Full Text]

28. Suzuki M, Naruse K, Asano Y, Okamoto T, Nishikimi N, Sakurai T, Nimura Y, Sokabe M. Up-regulation of integrin beta 3 expression by cyclic stretch in human umbilical endothelial cells. Biochem Biophys Res Commun. 1997;239:372–376.[Medline] [Order article via Infotrieve]

29. Reusch HP, Chan G, Ives HE, Nemenoff RA. Activation of JNK/SAPK and ERK by mechanical strain in vascular smooth muscle cells depends on extracellular matrix composition. Biochem Biophys Res Commun. 1997;237:239–244.[Medline] [Order article via Infotrieve]

30. Shrivastava A, Radziejewski C, Campbell E, Kovac L, McGlynn M, Ryan TE, Davis S, Glass DJ, Lemke G, Yancopoulos GD. An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors. Mol Cell. 1997;1:25–34.[Medline] [Order article via Infotrieve]

31. Abedi H, Dawes KE, Zachary I. Differential effects of platelet-derived growth factor BB on p125 focal adhesion kinase and paxillin tyrosine phosphorylation and on cell migration in rabbit aortic vascular smooth muscle cells and Swiss 3T3 fibroblasts. J Biol Chem. 1995;270:11367–11376.[Abstract/Free Full Text]

32. Schwartz MA, Lechene C. Adhesion is required for protein kinase-C-dependent activation of the Na+/H+ antiporter by platelet-derived growth factor. Proc Natl Acad Sci U S A. 1992;89:6138–6141.[Abstract/Free Full Text]

33. Sokabe M, Nunogaki K, Naruse K, Soga H. Mechanics of patch clamped and intact cell-membranes in relation to SA channel activation. Jpn J Physiol. 1993;43:S197–S204.

34. Davis MJ, Donovitz JA, Hood JD. Stretch-activated single-channel and whole cell currents in vascular smooth muscle cells. Am J Physiol. 1992;262:C1083–C1088.[Abstract/Free Full Text]

35. Lansman JB, Hallam TJ, Rink TJ. Single stretch-activated ion channels in vascular endothelial cells as mechanotransducers? Nature. 1987;325:811–813.[Medline] [Order article via Infotrieve]

36. Matsumoto H, Baron CB, Coburn RF. Smooth muscle stretch-activated phospholipase C activity. Am J Physiol. 1995;37:C458–C465.

37. Lucchesi PA, Bell JM, Willis LS, Byron KL, Corson MA, Berk BC. Ca²⁺-dependent mitogen-activated protein kinase activation in spontaneously hypertensive rat vascular smooth muscle defines a hypertensive signal transduction phenotype. Circ Res. 1996;78:962–970.[Abstract/Free Full Text]

38. Olesen SP, Clapham DE, Davies PF. Haemodynamic shear stress activates a K⁺ current in vascular endothelial cells. Nature. 1988;331:168–170.[Medline] [Order article via Infotrieve]

39. Ohno M, Gibbons GH, Dzau VJ, Cooke JP. Shear stress elevated endothelial cGMP: role of a potassium channel and G protein coupling. Circulation. 1993;88:193–197.[Abstract/Free Full Text]

40. Kirber MT, Ordway RW, Clapp LH, Walsh JV, Singer JJ. Both membrane stretch and fatty acids directly activate large conductance Ca²⁺-activated K⁺ channels in vascular smooth muscle cells. FEBS Lett. 1992;297:24–28.[Medline] [Order article via Infotrieve]

41. Takahashi T, Kawahara Y, Okuda M, Ueno H, Takeshita A, Yokoyama M. Angiotensin II stimulates mitogen-activated protein kinases and protein synthesis by a Ras-independent pathway in vascular smooth muscle cells. J Biol Chem. 1997;272:16018–16022.[Abstract/Free Full Text]

42. Traub O, Berk BC. Shear stress–mediated stimulation of ERK 1/2 in endothelial cells is regulated by a Na⁺ channel. Circulation. 1997;96(suppl I):I-50. Abstract.

43. Solowska J, Guan JL, Arcantonio EE, Trevithick JE, Buck CA, Hynes RO. Expression of normal and mutant avian integrin subunits in rodent cells. J Cell Biol. 1989;109:853–861.[Abstract/Free Full Text]

44. Otey CA, Pavalko FM, Burridge K. An interaction between alpha-actinin and the beta 1 integrin subunit in vitro. J Cell Biol. 1990;111:721–729.[Abstract/Free Full Text]

45. Horwitz A, Duggan K, Buck C, Beckerle MC, Burridge K. Interaction of plasma membrane fibronectin receptor with talin-a transmembrane linkage. Nature. 1986;320:531–533.[Medline] [Order article via Infotrieve]

46. Bennett JP, Zaner KS, Stossel TP. Isolation and some properties of macrophage alpha-actinin: evidence that it is not an actin gelling protein. Biochemistry. 1984;23:5081–5086.[Medline] [Order article via Infotrieve]

47. Burridge K, Mangeat P. An interaction between vinculin and talin. Nature. 1984;308:744–746.[Medline] [Order article via Infotrieve]

48. Belkin AM, Koteliansky VE. Interaction of iodinated vinculin, metavinculin and alpha-actinin with cytoskeletal proteins. FEBS Lett. 1987;220:291–294.[Medline] [Order article via Infotrieve]

49. Lo SH, Weisberg E, Chen LB. Tensin: a potential link between the cytoskeleton and signal transduction. Bioessays. 1994;16:817–823.[Medline] [Order article via Infotrieve]

50. Kornberg L, Earp HS, Parsons JT, Schaller M, Juliano RL. Cell adhesion or integrin clustering increases phosphorylation of a focal adhesion-associated tyrosine kinase. J Biol Chem. 1992;267:23439–23442.[Abstract/Free Full Text]

51. Burridge K, Turner CE, Romer LH. Tyrosine phosphorylation of paxillin and pp125FAK accompanies cell adhesion to extracellular matrix: a role in cytoskeletal assembly. J Cell Biol. 1992;119:893–903.[Abstract/Free Full Text]

52. Huang MM, Lipfert L, Cunningham M, Brugge JS, Ginsberg MH, Shattil SJ. Adhesive ligand binding to integrin alpha IIb beta 3 stimulates tyrosine phosphorylation of novel protein substrates before phosphorylation of pp125FAK. J Cell Biol. 1993;122:473–483.[Abstract/Free Full Text]

53. Li S, Kim M, Hu YL, Jalali S, Schlaepfer DD, Hunter T, Chien S, Shyy JY. Fluid shear stress activation of focal adhesion kinase: linking to mitogen-activated protein kinases. J Biol Chem. 1997;272: 30455–30462.

54. Takahashi M, Berk BC. Mitogen-activated protein kinase (ERK1/2) activation by shear stress and adhesion in endothelial cells: essential role for a herbimycin-sensitive kinase. J Clin Invest. 1996;98:2623–2631.[Medline] [Order article via Infotrieve]

55. Ishida T, Peterson TE, Kovach NL, Berk BC. MAP kinase activation by flow in endothelial cells: role of beta 1 integrins and tyrosine kinases. Circ Res. 1996;79:310–316.[Abstract/Free Full Text]

56. Hildebrand JD, Schaller MD, Parsons JT. Paxillin, a tyrosine phosphorylated focal adhesion-associated protein binds to the carboxyl terminal domain of focal adhesion kinase. Mol Biol Cell. 1995;6:637–647.[Abstract]

57. Chen HC, Appeddu PA, Parsons JT, Hildebrand JD, Schaller MD, Guan JL. Interaction of focal adhesion kinase with cytoskeletal protein talin. J Biol Chem. 1995;270:16995–16999.[Abstract/Free Full Text]

58. Schaller MD, Otey CA, Hildebrand JD, Parsons JT. Focal adhesion kinase and paxillin bind to peptides mimicking beta integrin cytoplasmic domains. J Cell Biol. 1995;130:1181–1187.[Abstract/Free Full Text]

59. Gilmore AP, Romer LH. Inhibition of focal adhesion kinase (FAK) signaling in focal adhesions decreases cell motility and proliferation. Mol Biol Cell. 1996;7:1209–1224.[Abstract]

60. Lyman S, Gilmore A, Burridge K, Gidwitz S, White GC. Integrin-mediated activation of focal adhesion kinase is independent of focal adhesion formation or integrin activation: studies with activated and inhibitory beta(3) cytoplasmic domain mutants. J Biol Chem. 1997;272:22538–22547.[Abstract/Free Full Text]

61. Miyamoto S, Teramoto H, Coso OA, Gutkind JS, Burbelo PD, Akiyama SK, Yamada KM. Integrin function: molecular hierarchies of cytoskeletal and signaling molecules. J Cell Biol. 1995;131:791–805.[Abstract/Free Full Text]

62. Flinn HM, Ridley AJ. Rho stimulates tyrosine phosphorylation of focal adhesion kinase, p130 and paxillin. J Cell Sci. 1996;109:1133–1141.[Abstract]

63. Schlaepfer DD, Hunter T. Focal adhesion kinase overexpression enhances Ras-dependent integrin signaling to ERK2/mitogen-activated protein kinase through interactions with and activation of c-Src. J Biol Chem. 1997;272:13189–13195.[Abstract/Free Full Text]

64. Chappel J, Ross FP, Abu-Ame Y, Shaw A, Teitelbaum SL. 1,25-Dihydroxyvitamin D3 regulates pp60c-Src activity and expression of a pp60c-Src activating phosphatase. J Cell Biochem. 1997;67:432–438.[Medline] [Order article via Infotrieve]

65. Seger R, Krebs EG. The MAPK signaling cascade. FASEB J. 1995;9:726–735.[Abstract]

66. Eppert K, Scherer SW, Ozcelik H, Pirone R, Hoodless P, Kim H, Tsui LC, Bapat B, Gallinger S, Andrulis IL, Thomsen GH, Wrana JL, Attisano L. MADR2 maps to 18q21 and encodes a TGFß-regulated MAD-related protein that is functionally mutated in colorectal carcinoma. Cell. 1996;86:543–552.[Medline] [Order article via Infotrieve]

67. Zhang ZH, Vuori K, Wang HG, Reed JC, Ruoslahti E. Integrin activation by R-Ras. Cell. 1996;85:61–69.[Medline] [Order article via Infotrieve]

68. Gimbrone MA, Nagel T, Topper JN. Biomechanical activation: an emerging paradigm in endothelial adhesion biology. J Clin Invest. 1997;99:1809–1813.[Medline] [Order article via Infotrieve]

69. Li YS, Shyy JYJ, Li S, Lee JD, Su B, Karin M, Chien S. The Ras-JNK pathway is involved in shear-induced gene expression. Mol Cell Biol. 1996;16:5947–5954.[Abstract/Free Full Text]

70. Tseng H, Peterson TE, Berk BC. Fluid shear stress stimulates mitogen-activated protein kinase in endothelial cells. Circ Res. 1995;77:869–878.[Abstract/Free Full Text]

71. Birukov KG, Lehoux S, Birukova AA, Merval R, Tkachuk VA, Tedgui A. Increased pressure induces sustained protein kinase C–independent herbimycin A–sensitive activation of extracellular signal–regulated kinase 1/2 in the rabbit aorta in organ culture. Circ Res. 1997;81:895–903.[Abstract/Free Full Text]

72. Xu Q, Liu Y, Gorospe M, Udelsman R, Holbrook NJ. Acute hypertension activates mitogen-activated protein kinases in arterial wall. J Clin Invest. 1996;97:508–514.[Medline] [Order article via Infotrieve]

73. Lille S, Daum G, Clowes MM, Clowes AW. The regulation of p42/p44 mitogen-activated protein kinases in the injured rat carotid artery. J Surg Res. 1997;70:178–186.[Medline] [Order article via Infotrieve]

74. Pyles JM, March KL, Franklin M, Mehdi K, Wilensky RL, Adam LP. Activation of MAP kinase in vivo follows balloon overstretch injury of porcine coronary and carotid arteries. Circ Res. 1997;81:904–910.[Abstract/Free Full Text]

75. Masumoto N, Nakayama K, Oyabe A, Uchino M, Ishii K, Obara K, Tanabe Y. Specific attenuation of the pressure-induced contraction of rat cerebral artery by herbimycin A. Eur J Pharmacol. 1997;330:55–63.[Medline] [Order article via Infotrieve]

76. Wary KK, Mainiero F, Isakoff SJ, Marcantonio EE, Giancotti FG. The adaptor protein Shc couples a class of integrins to the control of cell cycle progression. Cell. 1996;87:733–743.[Medline] [Order article via Infotrieve]

77. Alvarez E, Northwood IC, Gonzalez FA, Latour DA, Seth A, Abate C, Curran T, Davis RJ. Pro-Leu-Ser/Thr-Pro is a consensus primary sequence for substrate protein phosphorylation: characterization of the phosphorylation of c-myc and c-jun proteins by an epidermal growth factor receptor threonine 669 protein kinase. J Biol Chem. 1991;266:15277–15285.[Abstract/Free Full Text]

78. Whitmarsh AJ, Shore P, Sharrocks AD, Davis RJ. Integration of MAP kinase signal transduction pathways at the serum response element. Science. 1995;269:403–407.[Abstract/Free Full Text]

79. Brunn GJ, Hudson CC, Sekulic A, Williams JM, Hosoi H, Houghton PJ, Lawrence JC Jr, Abraham RT. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science. 1997;277:99–101.[Abstract/Free Full Text]

80. Proud CG. Turned on by insulin. Nature. 1994;371:747–748.[Medline] [Order article via Infotrieve]

81. Watson MH, Venance SL, Pang SC, Mak AS. Smooth muscle cell proliferation: expression and kinases activities of p34cdc2 and mitogen-activated protein kinase homologues. Circ Res. 1993;73:109–117.[Abstract]

82. Bornfeldt KE, Campbell JS, Koyama H, Argast GM, Leslie CC, Raines EW, Krebs EG, Ross R. The mitogen-activated protein kinase pathway can mediate growth inhibition and proliferation in smooth muscle cells: dependence on the availability of downstream targets. J Clin Invest. 1997;100:875–885.[Medline] [Order article via Infotrieve]

83. Davis RJ. The mitogen-activated protein kinase signal transduction pathway. J Biol Chem. 1993;268:14553–14556.[Free Full Text]

84. Dennis EA. Diversity of group types, regulation, and function of phospholipase A2. J Biol Chem. 1994;269:13057–13060.[Free Full Text]

85. Adam LP, Franklin MT, Raff GJ, Hathaway DR. Activation of mitogen-activated protein kinase in porcine carotid arteries. Circ Res. 1995;76:183–190.[Abstract/Free Full Text]

86. 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]

87. Hughes PE, Renshaw MW, Pfaff M, Forsyth J, Keivens VM, Schwartz MA, Ginsberg MH. Suppression of integrin activation: a novel function of a Ras/Raf-initiated MAP kinase pathway. Cell. 1997;88:521–530.[Medline] [Order article via Infotrieve]

88. Martin M, Vozenin MC, Gault N, Crechet F, Pfarr CM, Lefaix JL. Coactivation of AP-1 activity and TGF-ß1 gene expression in the stress response of normal skin cells to ionizing radiation. Oncogene. 1997;15:981–989.[Medline] [Order article via Infotrieve]

89. Hirakata M, Kaname S, Chung UG, Joki N, Hori Y, Noda M, Takuwa Y, Okazaki T, Fujita T, Katoh T, Kurokawa K. Tyrosine kinase dependent expression of TGF-ß induced by stretch in mesangial cells. Kidney Int. 1997;51:1028–1036.[Medline] [Order article via Infotrieve]

90. Noda M, Katoh T, Takuwa N, Kumada M, Kurokawa K, Takuwa Y. Synergistic stimulation of parathyroid hormone-related peptide gene expression by mechanical stretch and angiotensin II in rat aortic smooth muscle cells. J Biol Chem. 1994;269:17911–17917.[Abstract/Free Full Text]

91. Bardy N, Merval R, Benessiano J, Samuel J-L, Tedgui A. Pressure and angiotensin II synergistically induce aortic fibronectin expression in organ culture model of rabbit aorta: evidence for a pressure-induced tissue renin-angiotensin system. Circ Res. 1996;79:70–78.[Abstract/Free Full Text]

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

93. 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]

94. Timmermans PBMWM, Wong PC, Chiu AT, Herblin WF, Benfield P, Carini DJ, Lee RJ, Wexler RR, Saye JAM, Smith RD. Angiotensin-II receptors and angiotensin-II receptor antagonists. Pharmacol Rev. 1993;45:205–251.[Medline] [Order article via Infotrieve]

95. Giasson E, Meloche S. Role of p70 s6 protein kinase in angiotensin II-induced protein synthesis in vascular smooth muscle cells. J Biol Chem. 1995;270:5225–5231.[Abstract/Free Full Text]

96. Ishida M, Marrero MB, Schieffer B, Ishida T, Bernstein KE, Berk BC. Angiotensin II activates pp60(c-Src) in vascular smooth muscle cells. Circ Res. 1995;77:1053–1059.[Abstract/Free Full Text]

97. Miyamoto S, Teramoto H, Gutkind JS, Yamada KM. Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors. J Cell Biol. 1996;135:1633–1642.[Abstract/Free Full Text]

98. Bourcier T, Sukhova G, Libby P. The nuclear factor kappa-B signaling pathway participates in dysregulation of vascular smooth muscle cells in vitro and in human atherosclerosis. J Biol Chem. 1997;272:15817–15824.[Abstract/Free Full Text]

99. Siebenlist U, Franzoso G, Brown K. Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol. 1994;10:405–455.

100. Palombella VJ, Rando OJ, Goldberg AL, Maniatis T. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell. 1994;78:773–785.[Medline] [Order article via Infotrieve]

101. Hishikawa K, Oemar BS, Yang Z, Luscher TF. Pulsatile stretch stimulates superoxide production and activates nuclear factor-B in human coronary smooth muscle. Circ Res. 1997;81:797–803.[Abstract/Free Full Text]

102. Huot J, Houle F, Marceau F, Landry J. Oxidative stress-induced actin reorganization mediated by the p38 mitogen-activated protein kinase/heat shock protein 27 pathway in vascular endothelial cells. Circ Res. 1997;80:383–392.[Abstract/Free Full Text]

103. Topper JN, Cai JX, Qiu YB, Anderson KR, Xu YY, Deeds JD, Feeley R, Gimeno CJ, Woolf EA, Tayber O, Mays GG, Sampson BA, Schoen FJ, Gimbrone MA, Falb D. Vascular MADs: two novel MAD-related genes selectively inducible by flow in human vascular endothelium. Proc Natl Acad Sci U S A. 1997;94:9314–9319.[Abstract/Free Full Text]

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				K. Grote, I. Flach, M. Luchtefeld, E. Akin, S. M. Holland, H. Drexler, and B. Schieffer Mechanical Stretch Enhances mRNA Expression and Proenzyme Release of Matrix Metalloproteinase-2 (MMP-2) via NAD(P)H Oxidase-Derived Reactive Oxygen Species Circ. Res., June 13, 2003; 92 (11): e80 - e86. [Abstract] [Full Text] [PDF]

				H. Iwasaki, T. Yoshimoto, T. Sugiyama, and Y. Hirata Activation of Cell Adhesion Kinase {beta} by Mechanical Stretch in Vascular Smooth Muscle Cells Endocrinology, June 1, 2003; 144(6): 2304 - 2310. [Abstract] [Full Text] [PDF]

				J. Goldman, L. Zhong, and S. Q. Liu Degradation of alpha -actin filaments in venous smooth muscle cells in response to mechanical stretch Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1839 - H1847. [Abstract] [Full Text] [PDF]

				Y. E.G. Eskildsen-Helmond and M. J. Mulvany Pressure-Induced Activation of Extracellular Signal-Regulated Kinase 1/2 in Small Arteries Hypertension, April 1, 2003; 41(4): 891 - 897. [Abstract] [Full Text] [PDF]

				F. Wernig, M. Mayr, and Q. Xu Mechanical Stretch-Induced Apoptosis in Smooth Muscle Cells Is Mediated by {beta}1-Integrin Signaling Pathways Hypertension, April 1, 2003; 41(4): 903 - 911. [Abstract] [Full Text] [PDF]

				N. L. Parinandi, M. A. Kleinberg, P. V. Usatyuk, R. J. Cummings, A. Pennathur, A. J. Cardounel, J. L. Zweier, J. G. N. Garcia, and V. Natarajan Hyperoxia-induced NAD(P)H oxidase activation and regulation by MAP kinases in human lung endothelial cells Am J Physiol Lung Cell Mol Physiol, January 1, 2003; 284(1): L26 - L38. [Abstract] [Full Text] [PDF]

				A. L. Moore, M. W. Roe, R. F. Melnick, and S. D. Lidofsky Calcium Mobilization Evoked by Hepatocellular Swelling Is Linked to Activation of Phospholipase Cgamma J. Biol. Chem., September 6, 2002; 277(37): 34030 - 34035. [Abstract] [Full Text] [PDF]

				A. M. Brunsden, S. Jacob, K. D. Bardhan, and D. Grundy Mesenteric afferent nerves are sensitive to vascular perfusion in a novel preparation of rat ileum in vitro Am J Physiol Gastrointest Liver Physiol, September 1, 2002; 283(3): G656 - G665. [Abstract] [Full Text] [PDF]

				K. Isoda, K. Nishikawa, Y. Kamezawa, M. Yoshida, M. Kusuhara, M. Moroi, N. Tada, and F. Ohsuzu Osteopontin Plays an Important Role in the Development of Medial Thickening and Neointimal Formation Circ. Res., July 12, 2002; 91(1): 77 - 82. [Abstract] [Full Text] [PDF]

				R. S. T. LEUNG and T. DOUGLAS BRADLEY Sleep Apnea and Cardiovascular Disease Am. J. Respir. Crit. Care Med., December 15, 2001; 164(12): 2147 - 2165. [Full Text] [PDF]

				P. R. Standley, M. A. Stanley, and P. Senechal Activation of mitogenic and antimitogenic pathways in cyclically stretched arterial smooth muscle Am J Physiol Endocrinol Metab, December 1, 2001; 281(6): E1165 - E1171. [Abstract] [Full Text] [PDF]

				E. Songu-Mize, N. Sevieux, X. Liu, and M. Jacobs Effect of short-term cyclic stretch on sodium pump activity in aortic smooth muscle cells Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H2072 - H2078. [Abstract] [Full Text] [PDF]

				N. Kubis, A. Checoury, A. Tedgui, and B. I. Levy Adaptive common carotid arteries remodeling after unilateral internal carotid artery occlusion in adult patients Cardiovasc Res, June 1, 2001; 50(3): 597 - 602. [Abstract] [Full Text] [PDF]

				M. A. Martynowicz, B. J. Walters, and R. D. Hubmayr Mechanisms of recruitment in oleic acid-injured lungs J Appl Physiol, May 1, 2001; 90(5): 1744 - 1753. [Abstract] [Full Text] [PDF]

				L. Belhassen, G. Pelle, S. Sediame, D. Bachir, C. Carville, C. Bucherer, C. Lacombe, F. Galacteros, and S. Adnot Endothelial dysfunction in patients with sickle cell disease is related to selective impairment of shear stress-mediated vasodilation Blood, March 15, 2001; 97(6): 1584 - 1589. [Abstract] [Full Text] [PDF]

				J. P. M. Wesselman, A. D. Dobrian, S. D. Schriver, and R. L. Prewitt Src Tyrosine Kinases and Extracellular Signal-Regulated Kinase 1/2 Mitogen-Activated Protein Kinases Mediate Pressure-Induced C-Fos Expression in Cannulated Rat Mesenteric Small Arteries Hypertension, March 1, 2001; 37(3): 955 - 960. [Abstract] [Full Text] [PDF]

				I. Suzuma, Y. Hata, A. Clermont, F. Pokras, S. L. Rook, K. Suzuma, E. P. Feener, and L. P. Aiello Cyclic Stretch and Hypertension Induce Retinal Expression of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor--2: Potential Mechanisms for Exacerbation of Diabetic Retinopathy by Hypertension Diabetes, February 1, 2001; 50(2): 444 - 454. [Abstract] [Full Text]

				C.-B. Lanz, M. Causevic, C. Heiniger, F. J. Frey, B. M. Frey, and M. G. Mohaupt Fluid Shear Stress Reduces 11{beta}-Hydroxysteroid Dehydrogenase Type 2 Hypertension, January 1, 2001; 37(1): 160 - 169. [Abstract] [Full Text] [PDF]

				S. Lehoux, B. Esposito, R. Merval, L. Loufrani, and A. Tedgui Pulsatile Stretch-Induced Extracellular Signal-Regulated Kinase 1/2 Activation in Organ Culture of Rabbit Aorta Involves Reactive Oxygen Species Arterioscler Thromb Vasc Biol, November 1, 2000; 20(11): 2366 - 2372. [Abstract] [Full Text] [PDF]

				J. E. Rectenwald, L. L. Moldawer, T. S. Huber, J. M. Seeger, and C. K. Ozaki Direct Evidence for Cytokine Involvement in Neointimal Hyperplasia Circulation, October 3, 2000; 102(14): 1697 - 1702. [Abstract] [Full Text] [PDF]

				Y. Jiang, K. Kohara, and K. Hiwada Association Between Risk Factors for Atherosclerosis and Mechanical Forces in Carotid Artery Stroke, October 1, 2000; 31(10): 2319 - 2324. [Abstract] [Full Text] [PDF]

				K. Matrougui, Y. E. G. Eskildsen-Helmond, A. Fiebeler, D. Henrion, B. I. Levy, A. Tedgui, and M. J. Mulvany Angiotensin II Stimulates Extracellular Signal-Regulated Kinase Activity in Intact Pressurized Rat Mesenteric Resistance Arteries Hypertension, October 1, 2000; 36(4): 617 - 621. [Abstract] [Full Text] [PDF]

				M. R. Ward, G. Pasterkamp, A. C. Yeung, and C. Borst Arterial Remodeling : Mechanisms and Clinical Implications Circulation, September 5, 2000; 102(10): 1186 - 1191. [Full Text] [PDF]

				C. J. O'Callaghan and B. Williams Mechanical Strain-Induced Extracellular Matrix Production by Human Vascular Smooth Muscle Cells : Role of TGF-{beta}1 Hypertension, September 1, 2000; 36(3): 319 - 324. [Abstract] [Full Text] [PDF]

				A.'a. Zeidan, I. Nordstrom, K. Dreja, U. Malmqvist, and P. Hellstrand Stretch-Dependent Modulation of Contractility and Growth in Smooth Muscle of Rat Portal Vein Circ. Res., August 4, 2000; 87(3): 228 - 234. [Abstract] [Full Text] [PDF]

				O. Vallot, L. Combettes, P. Jourdon, J. Inamo, I. Marty, M. Claret, and A.-M. Lompre Intracellular Ca2+ Handling in Vascular Smooth Muscle Cells Is Affected by Proliferation Arterioscler Thromb Vasc Biol, May 1, 2000; 20(5): 1225 - 1235. [Abstract] [Full Text] [PDF]

				S. P. Schwarzacher, N. G. Uren, M. R. Ward, A. Schwarzkopf, N. Giannetti, S. Hunt, P. J. Fitzgerald, S. N. Oesterle, and A. C. Yeung Determinants of Coronary Remodeling in Transplant Coronary Disease : A Simultaneous Intravascular Ultrasound and Doppler Flow Study Circulation, March 28, 2000; 101(12): 1384 - 1389. [Abstract] [Full Text] [PDF]

				G. B. Chapman, W. Durante, J. D. Hellums, and A. I. Schafer Physiological cyclic stretch causes cell cycle arrest in cultured vascular smooth muscle cells Am J Physiol Heart Circ Physiol, March 1, 2000; 278(3): H748 - H754. [Abstract] [Full Text] [PDF]

				M. MAYR, C. LI, Y. ZOU, U. HUEMER, Y. HU, and Q. XU Biomechanical stress-induced apoptosis in vein grafts involves p38 mitogen-activated protein kinases FASEB J, February 1, 2000; 14(2): 261 - 270. [Abstract] [Full Text]

				H. Iwasaki, S. Eguchi, H. Ueno, F. Marumo, and Y. Hirata Mechanical stretch stimulates growth of vascular smooth muscle cells via epidermal growth factor receptor Am J Physiol Heart Circ Physiol, February 1, 2000; 278(2): H521 - H529. [Abstract] [Full Text] [PDF]

				M. Lauth, M.-M. Berger, M. Cattaruzza, and M. Hecker Elevated Perfusion Pressure Upregulates Endothelin-1 and Endothelin B Receptor Expression in the Rabbit Carotid Artery Hypertension, February 1, 2000; 35(2): 648 - 654. [Abstract] [Full Text] [PDF]

				M. Lauth, M.-M. Berger, M. Cattaruzza, and M. Hecker Pressure-Induced Upregulation of Preproendothelin-1 and Endothelin B Receptor Expression in Rabbit Jugular Vein In Situ : Implications for Vein Graft Failure? Arterioscler Thromb Vasc Biol, January 1, 2000; 20(1): 96 - 103. [Abstract] [Full Text] [PDF]

				L. Loufrani, S. Lehoux, A. Tedgui, B. I. Levy, and D. Henrion Stretch Induces Mitogen-Activated Protein Kinase Activation and Myogenic Tone Through 2 Distinct Pathways Arterioscler Thromb Vasc Biol, December 1, 1999; 19(12): 2878 - 2883. [Abstract] [Full Text] [PDF]

				F. C. Luft, E. Mervaala, D. N. Muller, V. Gross, F. Schmidt, J. K. Park, C. Schmitz, A. Lippoldt, V. Breu, R. Dechend, et al. Hypertension-Induced End-Organ Damage : A New Transgenic Approach to an Old Problem Hypertension, January 1, 1999; 33(1): 212 - 218. [Abstract] [Full Text] [PDF]

				I. Suzuma, K. Suzuma, K. Ueki, Y. Hata, E. P. Feener, G. L. King, and L. P. Aiello Stretch-induced Retinal Vascular Endothelial Growth Factor Expression Is Mediated by Phosphatidylinositol 3-Kinase and Protein Kinase C (PKC)-zeta but Not by Stretch-induced ERK1/2, Akt, Ras, or Classical/Novel PKC Pathways J. Biol. Chem., January 4, 2002; 277(2): 1047 - 1057. [Abstract] [Full Text] [PDF]

				M. E. Goldschmidt, K. J. McLeod, and W. R. Taylor Integrin-Mediated Mechanotransduction in Vascular Smooth Muscle Cells : Frequency and Force Response Characteristics Circ. Res., April 13, 2001; 88(7): 674 - 680. [Abstract] [Full Text] [PDF]

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