(Hypertension. 1995;25:913-917.)
© 1995 American Heart Association, Inc.
Articles |
Angiotensin II Increases Vascular Permeability Factor Gene Expression by Human Vascular Smooth Muscle Cells
From the Department of Medicine, University of Leicester (UK) School of Medicine.
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Abstract |
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Abstract Angiotensin II (Ang II) has been implicated in the pathogenesis of the vascular injury associated with hypertension and diabetes mellitus. Increased vascular permeability is an important early manifestation of endothelial dysfunction and the pathogenesis of atherosclerosis. How Ang II contributes to endothelial dysfunction and promotes an increase in vascular permeability is unknown but is classically attributed to its pressor actions. We demonstrate that human vascular smooth muscle cells express abundant mRNA for vascular permeability/endothelial growth factor. Vascular permeability factor is a 34- to 42-kD glycoprotein that markedly increases vascular endothelial permeability and is a potent endothelial mitogen. Ang II potently induced a concentration-dependent (maximal, 10-7 mol/L) and time-dependent increase in vascular permeability factor mRNA expression by human vascular smooth muscle cells that was maximal after 3 hours and diminished by 24 hours. Ang II–induced vascular permeability factor mRNA expression by human vascular smooth muscle cells was inhibited by the specific Ang II receptor antagonist losartan (DuP 753), confirming that this is an Ang II receptor subtype 1–mediated event. These results describe a new action of Ang II on human vascular smooth muscle, notably the induction of vascular permeability factor mRNA expression. The wide spectrum and potent activity of vascular permeability factor suggest a novel mechanism whereby Ang II could locally and directly influence the permeability, growth, and function of the vascular endothelium independent of changes in hemodynamics.
Key Words: angiotensin II • capillary permeability • endothelial growth factors • muscle, smooth, vascular • gene expression
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Introduction |
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An early and important event in the pathogenesis of atherosclerosis is the development of endothelial dysfunction, a prominent manifestation of which is an increase in endothelial permeability to circulating macromolecules.1 It has long been proposed that in hypertensive states, increased vascular permeability occurs as a direct consequence of pressure-mediated mechanical injury to the endothelium.2 Morphological studies, however, are not consistent with this conclusion, having shown that the dysfunctional endothelial cell layer is intact.1 This has prompted the search for additional factors that may adversely influence endothelial permeability. In this regard, it has been proposed that a humoral permeabilizing factor exists that acts in concert with elevated blood pressure to increase vascular permeability.1 3 Consistent with this hypothesis, Asscher and Anson4 reported that the injection of renal extracts caused serous effusions and vascular lesions in rats that they attributed to a renal-derived "vascular permeability factor" (VPF). Subsequently, the active component of the renal extract was shown to be renin, and the permeabilizing actions of the extract were reproduced in animals by infusion of angiotensin II (Ang II).5 6 It was thus concluded that Ang II increases vascular permeability and injury via its pressor action.6
Increasing evidence supports a role for Ang II in the pathogenesis of vascular injury via mechanisms that are independent of its pressor activity. Ang II induces the expression of a wide spectrum of genes in vascular tissue, suggesting a key role for Ang II in regulating vascular structure and function.7 8 Whether the action of Ang II to increase vascular permeability could also be attributed to Ang II–induced vascular expression of VPFs is unknown.
A potent VPF has recently been described that is expressed and secreted at high levels by various cells of human and animal origin.9 VPF is also a powerful endothelial cell–specific mitogen and also named vascular endothelial cell growth factor, or VEGF (referred to herein as VPF).9 10 11 VPF is a 34- to 42-kD heparin-binding, dimeric, disulfide-bonded glycoprotein that binds to two high-affinity receptors each with tyrosine kinase domains, predominantly located on vascular endothelium.9 12 13 14 15 Alternative splicing of mRNA yields four different VPF transcripts encoding polypeptides of 206, 189, 165, and 121 amino acids.16 17 VPF is among the most potent vascular permeability–enhancing factors thus far identified, and on a molar basis, it is 50 000 times as potent as histamine.18 This potent action of VPF makes it an attractive candidate as a mediator of normal and pathological changes in vascular permeability. In this regard, a logical site for VPF expression in humans would be vascular smooth muscle cells (VSMCs), which are in close proximity to the endothelium in blood vessels and would allow VPF to act as a paracrine regulator of vascular function. However, the potential significance of VPF with regard to vascular biology and its potential modulation by vasoactive peptides such as Ang II has remained undefined.
The present study tests the hypothesis that human VSMCs express VPF mRNA and that Ang II acts as an independent humoral modulator of VPF mRNA expression by human vascular smooth muscle. Such a finding would describe a new action of Ang II and provide a novel mechanism whereby Ang II could powerfully influence vascular endothelial permeability independent of its pressor activity.
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Methods |
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Human VSMC Culture
VSMCs were cultured from human aortic tissue obtained fresh from cadavers at the time kidneys were procured for renal transplantation. The vascular smooth muscle layer was identified by dissection, diced, and digested in collagenase for 2 hours as previously described.19 20 The resulting cell suspension was centrifuged; resuspended in Ham's F-12 medium (Sigma Chemical Co) supplemented with 20% fetal bovine serum (FBS) (Life Technologies), 0.5% chick embryo extract (Life Technologies), 2 mmol/L L-glutamine, and antibiotics; and cultured in 100-mm tissue culture plates in humidified air supplemented with 5% CO2. The cell monolayers were extensively characterized to be well differentiated VSMCs on the basis of light and electron microscopic morphology and immunohistochemistry. When confluent, VSMC monolayers were passaged every 6 to 7 days after trypsinization and were used for experiments from the second to sixth passages.
Polymerase Chain Reaction Amplification and cDNA Probes
For detection of VPF mRNA, a 204-bp cDNA fragment was generated
from human kidney RNA with the use of two oligonucleotide primers that
were based on the human VPF cDNA sequence16 : (1)
(forward): 5'-CGCGGATCCAGGAGTACCCTGATATGAG-3' and (2) (reverse):
5'-CCGGAATTCACATTTGTTGTGCTGT-3'. The primers have built-in restriction
sites, BamHI in primer 1 and EcoRI in primer 2,
at their 5' ends to facilitate subcloning. For polymerase chain
reaction (PCR) amplification, 0.1 µg total RNA from human kidney was
annealed with random hexanucleotides and reverse transcribed for 30
minutes at 42°C with the use of 100u reverse transcriptase (Life
Technologies) in a volume of 20 µL. The reaction mixture was heated
to 95°C for 10 minutes before the addition of the PCR primers and
Taq polymerase (Biotaq, Bioline Corp) in a final volume of
100 µL. PCR amplification was performed on 100-µL samples with the
use of a DNA thermal cycler (Perkin-Elmer 480). Amplification was
carried out for 30 to 35 cycles (1 minute at 94°C to separate, 1
minute at 55°C to anneal, and 1 minute at 72°C to extend). The
resulting 204-bp cDNA fragment was subcloned into the polylinker region
of pBluescript II SK(+). The identity of the cloned human insert was
confirmed by Sanger dideoxy-DNA sequencing and found to be identical to
the previously reported human VPF sequence. The 204-bp fragment
generated in this way is also common to all known VPF splicing
variants.
Northern Analysis
The human VPF cDNA insert was radiolabeled with
[
-32P]dCTP (Amersham) to a specific activity of
approximately 2x109 cpm/µg DNA using the random primer
labeling system (Life Technologies). Typically, 20 ng of labeled probe
was used for each 70-cm2 filter. Total cellular RNA was
prepared from cultured human VSMCs with the one-step
guanidinium–phenol chloroform purification method.21 RNA
samples (15 to 25 µg per lane) were size-fractionated on 1.2%
agarose containing 6% formaldehyde and blotted onto Hybond nylon
membranes (Amersham). Hybridization was carried out for 18 hours at
42°C in 50% formamide, 5% SSPE, 2.5% Denhardt's solution, 0.1%
sodium dodecyl sulfate, and 10% dextran sulfate. Final washes were
carried out at high stringency (0.1x SSC and 0.1% sodium dodecyl
sulfate at 65°C). The blots were exposed to Kodak XAR2 film with an
intensifying screen at -72°C for 24 hours. To control for total mRNA
content and lack of degradation, the blots were subsequently stripped
and hybridized with a cDNA fragment for human GAPDH (No. 9805/1,
Clontech). The resulting autoradiographs were subjected to
densitometric analysis (LKB Gelscan, Pharmacia) to quantify the
ratio of VPF to GAPDH mRNA. Statistical differences in the VPF-GAPDH
ratio were defined using ANOVA with a Bonferroni correction. Results
are given as mean±SD unless indicated otherwise; a value of
P<.05 was considered significant.
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Results |
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Effect of Ang II on VPF mRNA Expression by Human VSMCs
Northern blots of RNA isolated from confluent human VSMCs were probed with the 204-bp VPF cDNA fragment that is specific for and complementary to all known variants of VPF mRNA. In human VSMCs, this radiolabeled cDNA probe hybridized with a single 4.2-kb VPF transcript. In preliminary experiments, we demonstrated that the abundance of VPF mRNA expressed by human VSMCs was strongly influenced by the FBS concentration in the overlying culture medium, VPF mRNA being less abundant when human VSMCs were rendered quiescent by 48 hours of exposure to serum-deprived (1% FBS) culture medium.22 The effect of Ang II on steady-state VPF mRNA levels was thus examined in confluent monolayers of quiescent human VSMCs. Supplementation of serum-deprived culture medium with Ang II (10-7 mol/L) resulted in a rapid, marked, and significant increase in VPF mRNA expression (Fig 1). This effect of Ang II was maximal after 3 hours and progressively diminished with increasing time exposure up to 24 hours. Densitometric analysis of autoradiographs from repeated experiments (n=4) revealed a consistent response to Ang II (VPF mRNA–GAPDH mRNA ratio: 1.9±0.2 versus 8.0±1.4, 0 versus 3 hours, P<.01, mean±SEM).
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Concentration Dependency of Ang II–Induced VPF mRNA Expression
Maximal Ang II–induced VPF mRNA expression occurred at 3 hours;
therefore, the 3-hour time point was used to define the concentration
dependency of Ang II–induced VPF mRNA expression by human VSMCs. Fig 2 shows that at this time point, VPF mRNA expression was
Ang II concentration dependent and maximally stimulated by Ang II
concentrations of 10-6 to 10-7 mol/L.
Densitometric analysis of the VPF mRNA–GAPDH mRNA ratio (n=4)
revealed a consistent, maximal, and significant increase in VPF mRNA
expression with Ang II concentrations of 10-7 mol/L (VPF
mRNA–GAPDH mRNA ratio: 1.3±0.3 versus 7.2±0.9, control versus
10-7 mol/L Ang II, P<.01).
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Identifying the Ang II Receptor Subtype Responsible for Ang
II–Induced Increases in VPF mRNA Expression
At least two subtypes of the Ang II receptor have been
identified in human tissues, AT1 and
AT2.23 24 The AT1 receptor is by
far the most abundant on human VSMCs, where it is responsible for all
of the recognized actions of Ang II.24 The function of the
AT2 receptor in human VSMCs is unclear. The AT1
receptor can be selectively and specifically inhibited by the
nonpeptide imidazole derivative losartan (DuP 753).23 Fig 3 shows that supplementation of FBS-deprived culture
medium with losartan (10-5 mol/L) alone had no
effect on the basal expression of VPF mRNA by human VSMCs. However,
losartan did inhibit the Ang II–induced increase in VPF mRNA
expression by human VSMCs. Densitometric analysis of
autoradiographs from further experiments (n=4) confirmed a consistent,
complete inhibition of the Ang II–induced increase in VPF mRNA
expression by losartan in human VSMCs (VPF mRNA–GAPDH ratio: 1.5±0.3
versus 7.9±1.7 and 2.3± 0.9, control versus Ang II alone
[P<.01] and Ang II plus losartan
[P<.8]).These results confirm that the action of Ang II
to stimulate an increase in VPF mRNA abundance in human VSMCs is
receptor mediated and occurs via the AT1 receptor.
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Discussion |
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The present study demonstrates a novel action of Ang II on human vascular tissue, notably a direct and potent regulation of VPF gene expression. Ang II–induced VPF mRNA expression in human VSMCs is rapid and maximal within 3 to 6 hours and diminishes by 12 hours. The rapidity of this response is consistent with previous reports of Ang II–induced gene expression in VSMCs; for example, Ang II induces platelet-derived growth factor A–chain mRNA expression in VSMCs, which is maximal at 9 hours.7 The mechanism underlying the progressive diminution of Ang II–induced VPF mRNA expression over time is unclear. It may represent tachyphylaxis to continuous Ang II stimulation or reflect progressive peptidase-mediated neutralization of Ang II, which is known to occur in cell culture media. Further studies are required to establish the precise mechanism. The Ang II concentration required to maximally induce VPF mRNA expression (10-7 mol/L) in vitro is considerably higher than normal circulating levels of Ang II in vivo. Nevertheless, these concentrations are consistent with those required to reproduce the physiological actions of Ang II in VSMCs in vitro.20 Moreover, it is likely that tissue levels of Ang II are considerably higher than circulating levels.25
The present study has not defined the mechanism whereby Ang II regulates VPF gene expression. The Ang II–induced increase in steady-state VPF mRNA levels could relate to either an increase in VPF gene transcription or Ang II–induced stabilization of VPF mRNA. Studies are ongoing to determine the relative importance of each mechanism in regulating VPF mRNA levels in human VSMCs in response to Ang II and a variety of other stimuli.
This study has focused on the regulation of VPF mRNA levels in human VSMCs, and VPF peptide production in response to Ang II was not measured. Nevertheless, as expected for a secreted protein, in all previous reports in which steady-state VPF mRNA levels are increased, there has been a corresponding increase in VPF peptide production.9 This implies that the abundant expression of VPF mRNA in human VSMCs and its potent modulation by Ang II are likely to be biologically significant.
The observations reported herein have important implications for the role of Ang II in the normal physiology of blood vessels and the pathogenesis of vascular injury. Although Ang II has been classically defined as an endocrine substance acting on blood pressure regulation, many tissues express endogenous renin-angiotensin system activity, implying that locally generated Ang II is involved in complex autocrine/paracrine regulatory mechanisms.25 Human blood vessels contain all components of the renin-angiotensin system25 26 27 ; it is thus conceivable that locally generated Ang II could act as an autocrine hormone to regulate VPF production within the vascular smooth muscle of human blood vessels, thereby allowing VPF to act as a paracrine hormone to regulate the permeability of the overlying endothelium. This novel concept suggests a mechanism whereby Ang II could directly influence vascular permeability independent of its actions on blood pressure or microcirculatory hemodynamics.
In addition to its potent effects on vascular permeability, VPF is also a powerful endothelial cell–specific mitogen in vitro and is expressed in a variety of highly vascularized tissues where its expression is temporally and spatially related to angiogenesis.9 10 11 20 21 22 23 24 25 26 27 28 29 30 Furthermore, the application of VPF to biological membranes such as the chorioallantoic membrane promotes neovascularization,9 suggesting an important role for VPF as a physiological mediator of angiogenesis in vivo. The abundant expression of VPF mRNA by human VSMCs suggests that Ang II–induced VPF production could play an important role in the normal growth and repair of the overlying vascular endothelium in vivo.
The capacity of VPF to function simultaneously as a potent vascular permeabilizing agent and mitogen suggests that Ang II–induced increases in VPF production could also play a key role in the vascular injury that complicates disease states such as diabetes mellitus. Increased vascular permeability and neovascularization are prominent features of the microvascular complications of diabetes mellitus. Recent studies have shown that elevated plasma prorenin levels identify diabetic subjects who are at high risk for the development of diabetic microvascular complications such as proliferative retinopathy and nephropathy.31 Prorenin levels are also markedly increased in the vitreous fluid extracted from the eyes of patients with proliferative retinopathy.32 It is intriguing that in a recent report, VPF levels were markedly elevated in the vitreous fluid of eyes from diabetic patients with proliferative retinopathy compared with the vitreous fluid from the eyes of diabetic patients without active retinopathy.33 We propose that these observations suggest a novel mechanism whereby increased circulating or local production of Ang II could directly influence vascular permeability and neovascularization in diabetic patients via Ang II–induced VPF production.
In addition to the aforementioned changes in endothelial permeability and growth, VPF has been reported to promote the release of Von Willebrand factor and tissue factor, generating a procoagulant state on the endothelial surface,34 35 and also to induce monocyte activation and migration to the endothelium.35 Each of these events is recognized to be important in the initiation of endothelial dysfunction and the early pathogenesis of atherosclerosis.1 The present study thus suggests an additional mechanism whereby increased systemic or local Ang II production could contribute to a spectrum of endothelial dysfunction that could ultimately play a role in the pathogenesis of vascular disease in a variety of disease states.
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Acknowledgments |
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This work was funded by grants IRF296 and PG92/61 from the British Heart Foundation. We thank Prof John D. Swales for his helpful advice.
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Footnotes |
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Reprint requests to Dr Bryan Williams, Department of Medicine, Clinical Sciences Building, Leicester Royal Infirmary, PO Box 65, Leicester, LE2 7LX, UK.
This work was presented as an oral communication to the American Blood Pressure Council Meeting, Chicago, Ill, September 1994.
Received November 22, 1994; first decision December 9, 1994; accepted January 13, 1995.
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 A. R. Albig and W. P. Schiemann Identification and Characterization of Regulator of G Protein Signaling 4 (RGS4) as a Novel Inhibitor of Tubulogenesis: RGS4 Inhibits Mitogen-activated Protein Kinases and Vascular Endothelial Growth Factor Signaling Mol. Biol. Cell, February 1, 2005; 16(2): 609 - 625. [Abstract] [Full Text] [PDF]
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T. Ichiki Role of Renin Angiotensin System in Angiogenesis: It Is Still Elusive Arterioscler Thromb Vasc Biol, April 1, 2004; 24(4): 622 - 624. [Full Text] [PDF]
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Y. Watanabe, K. Shibata, F. Kikkawa, H. Kajiyama, K. Ino, A. Hattori, M. Tsujimoto, and S. Mizutani Adipocyte-Derived Leucine Aminopeptidase Suppresses Angiogenesis in Human Endometrial Carcinoma via Renin-Angiotensin System Clin. Cancer Res., December 15, 2003; 9(17): 6497 - 6503. [Abstract] [Full Text] [PDF]
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R. Noguchi, H. Yoshiji, S. Kuriyama, J. Yoshii, Y. Ikenaka, K. Yanase, T. Namisaki, M. Kitade, M. Yamazaki, A. Mitoro, et al. Combination of Interferon-{beta} and the Angiotensin-Converting Enzyme Inhibitor, Perindopril, Attenuates Murine Hepatocellular Carcinoma Development and Angiogenesis Clin. Cancer Res., December 1, 2003; 9(16): 6038 - 6045. [Abstract] [Full Text] [PDF]
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 D. J. Kelly, C. Hepper, L. L. Wu, A. J. Cox, and R. E. Gilbert Vascular endothelial growth factor expression and glomerular endothelial cell loss in the remnant kidney model Nephrol. Dial. Transplant., July 1, 2003; 18(7): 1286 - 1292. [Abstract] [Full Text] [PDF]
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 D.C Felmeden, A.D Blann, and G.Y.H Lip Angiogenesis: basic pathophysiology and implications for disease Eur. Heart J., April 1, 2003; 24(7): 586 - 603. [Full Text] [PDF]
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 J. Katada, M. Muramatsu, I. Hayashi, M. Tsutsumi, Y. Konishi, and M. Majima Significance of Vascular Endothelial Cell Growth Factor Up-Regulation Mediated via a Chymase-Angiotensin-Dependent Pathway during Angiogenesis in Hamster Sponge Granulomas J. Pharmacol. Exp. Ther., September 1, 2002; 302(3): 949 - 956. [Abstract] [Full Text] [PDF]
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D.-H. Kang, T. Nakagawa, L. Feng, and R. J. Johnson Nitric Oxide Modulates Vascular Disease in the Remnant Kidney Model Am. J. Pathol., July 1, 2002; 161(1): 239 - 248. [Abstract] [Full Text] [PDF]
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D.-H. Kang, J. Kanellis, C. Hugo, L. Truong, S. Anderson, D. Kerjaschki, G. F. Schreiner, and R. J. Johnson Role of the Microvascular Endothelium in Progressive Renal Disease J. Am. Soc. Nephrol., March 1, 2002; 13(3): 806 - 816. [Abstract] [Full Text] [PDF]
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 J. L. Segar, G. B. Dalshaug, K. A. Bedell, O. M. Smith, and T. D. Scholz Angiotensin II in cardiac pressure-overload hypertrophy in fetal sheep Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2001; 281(6): R2037 - R2047. [Abstract] [Full Text] [PDF]
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S. Bassus, O. Herkert, N. Kronemann, A. Gorlach, D. Bremerich, C. M. Kirchmaier, R. Busse, and V. B. Schini-Kerth Thrombin Causes Vascular Endothelial Growth Factor Expression in Vascular Smooth Muscle Cells: Role of Reactive Oxygen Species Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1550 - 1555. [Abstract] [Full Text] [PDF]
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H. Yoshiji, S. Kuriyama, M. Kawata, J. Yoshii, Y. Ikenaka, R. Noguchi, T. Nakatani, H. Tsujinoue, and H. Fukui The Angiotensin-I-converting Enzyme Inhibitor Perindopril Suppresses Tumor Growth and Angiogenesis: Possible Role of the Vascular Endothelial Growth Factor Clin. Cancer Res., April 1, 2001; 7(4): 1073 - 1078. [Abstract] [Full Text]
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 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]
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M. Sorooshian, J. L. Olson, and T. W. Meyer Effect of Angiotensin II Blockade on Renal Injury in Mineralocorticoid-Salt Hypertension Hypertension, October 1, 2000; 36(4): 569 - 574. [Abstract] [Full Text] [PDF]
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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]
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A. Otani, H. Takagi, H. Oh, K. Suzuma, M. Matsumura, E. Ikeda, and Y. Honda Angiotensin II-Stimulated Vascular Endothelial Growth Factor Expression in Bovine Retinal Pericytes Invest. Ophthalmol. Vis. Sci., April 1, 2000; 41(5): 1192 - 1199. [Abstract] [Full Text]
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A. G Stanley, H. Patel, A. L Knight, and B. Williams Mechanical strain-induced human vascular matrix synthesis: The role of angiotensin II Journal of Renin-Angiotensin-Aldosterone System, March 1, 2000; 1(1): 32 - 35. [Abstract] [PDF]
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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]
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 N. Kronemann, A. Bouloumie, S. Bassus, C. M. Kirchmaier, R. Busse, and V. B. Schini-Kerth Aggregating Human Platelets Stimulate Expression of Vascular Endothelial Growth Factor in Cultured Vascular Smooth Muscle Cells Through a Synergistic Effect of Transforming Growth Factor-{beta}1 and Platelet-Derived Growth FactorAB Circulation, August 24, 1999; 100(8): 855 - 860. [Abstract] [Full Text] [PDF]
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I. Hernandez, L. F. Carbonell, T. Quesada, and F. J. Fenoy Role of angiotensin II in modulating the hemodynamic effects of nitric oxide synthesis inhibition Am J Physiol Regulatory Integrative Comp Physiol, July 1, 1999; 277(1): R104 - R111. [Abstract] [Full Text] [PDF]
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J.-E. Fabre, A. Rivard, M. Magner, M. Silver, and J. M. Isner Tissue Inhibition of Angiotensin-Converting Enzyme Activity Stimulates Angiogenesis In Vivo Circulation, June 15, 1999; 99(23): 3043 - 3049. [Abstract] [Full Text] [PDF]
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G. GRUDEN, S. THOMAS, D. BURT, W. ZHOU, G. CHUSNEY, L. GNUDI, and G. VIBERTI Interaction of Angiotensin II and Mechanical Stretch on Vascular Endothelial Growth Factor Production by Human Mesangial Cells J. Am. Soc. Nephrol., April 1, 1999; 10(4): 730 - 737. [Abstract] [Full Text]
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C. PUPILLI, L. LASAGNI, P. ROMAGNANI, F. BELLINI, M. MANNELLI, N. MISCIGLIA, C. MAVILIA, U. VELLEI, D. VILLARI, and M. SERIO Angiotensin II Stimulates the Synthesis and Secretion of Vascular Permeability Factor/Vascular Endothelial Growth Factor in Human Mesangial Cells J. Am. Soc. Nephrol., February 1, 1999; 10(2): 245 - 255. [Abstract] [Full Text]
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R. M. Touyz, G. He, L.-Y. Deng, and E. L. Schiffrin Role of Extracellular Signal-Regulated Kinases in Angiotensin II–Stimulated Contraction of Smooth Muscle Cells From Human Resistance Arteries Circulation, January 26, 1999; 99(3): 392 - 399. [Abstract] [Full Text] [PDF]
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M. Inoue, H. Itoh, M. Ueda, T. Naruko, A. Kojima, R. Komatsu, K. Doi, Y. Ogawa, N. Tamura, K. Takaya, et al. Vascular Endothelial Growth Factor (VEGF) Expression in Human Coronary Atherosclerotic Lesions : Possible Pathophysiological Significance of VEGF in Progression of Atherosclerosis Circulation, November 17, 1998; 98(20): 2108 - 2116. [Abstract] [Full Text] [PDF]
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M. L. Goalstone, R. Natarajan, P. R. Standley, M. F. Walsh, J. W. Leitner, K. Carel, S. Scott, J. Nadler, J. R. Sowers, and B. Draznin Insulin Potentiates Platelet-Derived Growth Factor Action in Vascular Smooth Muscle Cells Endocrinology, October 1, 1998; 139(10): 4067 - 4072. [Abstract] [Full Text] [PDF]
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A. Matsuura, W. Yamochi, K.-i. Hirata, S. Kawashima, and M. Yokoyama Stimulatory Interaction Between Vascular Endothelial Growth Factor and Endothelin-1 on Each Gene Expression Hypertension, July 1, 1998; 32(1): 89 - 95. [Abstract] [Full Text] [PDF]
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I. Hernandez, J. L. Delgado, L. F. Carbonell, M. C. Perez, and T. Quesada Hemodynamic effect of 17beta -estradiol in absence of NO in ovariectomized rats: role of angiotensin II Am J Physiol Regulatory Integrative Comp Physiol, April 1, 1998; 274(4): R970 - R978. [Abstract] [Full Text] [PDF]
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Y. Kim, R. Y. Imdad, A. H. Stephenson, R. S. Sprague, and A. J. Lonigro Vascular Endothelial Growth Factor mRNA in Pericytes Is Upregulated by Phorbol Myristate Acetate Hypertension, January 1, 1998; 31(1): 511 - 515. [Abstract] [Full Text] [PDF]
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R. Natarajan, W. Bai, L. Lanting, N. Gonzales, and J. Nadler Effects of high glucose on vascular endothelial growth factor expression in vascular smooth muscle cells Am J Physiol Heart Circ Physiol, November 1, 1997; 273(5): H2224 - H2231. [Abstract] [Full Text] [PDF]
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M. Guazzi, G. Marenzi, M. Alimento, M. Contini, and P. Agostoni Improvement of Alveolar–Capillary Membrane Diffusing Capacity With Enalapril in Chronic Heart Failure and Counteracting Effect of Aspirin Circulation, April 1, 1997; 95(7): 1930 - 1936. [Abstract] [Full Text]
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B. Erdmann, K. Fuxe, and D. Ganten Subcellular Localization of Angiotensin II Immunoreactivity in the Rat Cerebellar Cortex Hypertension, November 1, 1996; 28(5): 818 - 824. [Abstract] [Full Text]
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D. E. Richard, E. Berra, and J. Pouyssegur Nonhypoxic Pathway Mediates the Induction of Hypoxia-inducible Factor 1alpha in Vascular Smooth Muscle Cells J. Biol. Chem., August 25, 2000; 275(35): 26765 - 26771. [Abstract] [Full Text] [PDF]
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Q. Zhao, K. Egashira, S. Inoue, M. Usui, S. Kitamoto, W. Ni, M. Ishibashi, K.-i. Hiasa, T. Ichiki, M. Shibuya, et al. Vascular Endothelial Growth Factor Is Necessary in the Development of Arteriosclerosis by Recruiting/Activating Monocytes in a Rat Model of Long-Term Inhibition of Nitric Oxide Synthesis Circulation, March 5, 2002; 105(9): 1110 - 1115. [Abstract] [Full Text] [PDF]
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