Abstract 505: Specific Activation of the Ang all/AT1R-Jak2-Rho Kinase Pathway in Salt Sensitive but not in Salt Independent Hypertension: Clinical and Pathophysiologically Implications

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Kiranmia Chadipiralla ◽  
Ramiro Juncos ◽  
Ming-sheng Zhou ◽  
Leopoldo Raij
Keyword(s):  
Rho Kinase ◽  
No Production ◽  
Ang Ii ◽  
Dietary Salt ◽  
Main Determinant ◽  
Kinase Activation ◽  
Novel Studies ◽  
Salt Sensitive Hypertension ◽  
First Time ◽  
Kinase Pathway

In hypertension aortic (Ao) stiffness is a main determinant of increased systolic (SBP) and pulse- pressure (PP). Brachial and Ao SBP and PP often differ; Ao pressures predict cardiovascular events more accurately than brachial pressures. It is surmised that increased pressure-workload is cause and effect of Ao stiffening but the mechanisms involved are poorly understood. Rho Kinase is a master regulator of vascular tone and remodeling: In endothelium Rho kinase decreases eNOS expression and NO production. In VSMC Ang II/ AT1R specifically activates Rho Kinase via phosphorylation of Jak2 /Arhgef1 which phosphorylates (inhibits) myosin light chain phosphatase (MYPT1) thereby promoting vasoconstriction. Groups (n= 6) of Dahl SS (DS) rats fed either 0.5% or 4% NaCl diets for 10 weeks were matched with SHR of similar age (6 and 16weeks old) and SBP (147+8 & 211+7). Hypertensive DS rats, but not SHR showed increased Ao weight/length (17%, P<0.05) and left ventricle weight/ body weight ratios (16%, P<0.05). Compared to normotensive DS, Ao AT1Rs in hypertensive DS rose 230% accompanied by increased pJak2/Jak2 (3.5 fold) and pMYPT1/MYPT1 (3.95 fold) all p<0.05. Switch of hypertensive DS to a 0.5 % NaCl diet for 4 additional weeks did not reduce either SBP or the activated Ang l1/Rho Kinase pathways. The ARB Candesartan prevented Angll/AT1-Jak2-Rho Kinase activation in hypertensive DS fed 4% NaCl diet and normalized SBP, LVH and Ao weight/length in hypertensive DS switched to a 0,5% NaCl diet. Hypertensive SHR did not show Ao upregulation of AT1Rs or activation of the Angll/Jak2-Rho Kinase pathway. These studies show for the first time that in low renin salt sensitive hypertension there is specific Ao activation of the Ang II/Jak2-Rho Kinase pathway that is independent of the severity of SBP. Clinically the variable end-organ disease observed in individuals with similar severity of hypertension may be linked, at least in part, to genetically conditioned differences in Angll/AT1R, Jak-2 activation in response to high dietary salt. These novel studies extend and complement previous studies by us and others implicating abnormal bioactivity of NO and aldosterone in salt sensitive hypertension and unravel a new and intricate pathway in which Rho Kinase plays a pivotal role.

Salt-sensitive hypertension in ANP knockout mice is prevented by AT1 receptor antagonist losartan

1999 ◽  
Vol 277 (3) ◽  
pp. R624-R630 ◽  
Author(s):  
Luis G. Melo ◽  
Anthony T. Veress ◽  
Chee K. Chong ◽  
Uwe Ackermann ◽  
Harald Sonnenberg
Keyword(s):  
Receptor Antagonist ◽  
Knockout Mice ◽  
Plasma Renin ◽  
Plasma Catecholamine ◽  
Ang Ii ◽  
Dietary Salt ◽  
Water Control ◽  
Dietary Regimen ◽  
Arterial Blood ◽  
Salt Sensitive Hypertension

Mice harboring a functional deletion of the pro-atrial natriuretic peptide (ANP) gene (−/−) develop salt-sensitive hypertension relative to their wild-type (+/+) counterparts after prolonged (>1 wk) maintenance on high-salt (HS, 8% NaCl) diet. We reported recently that the sensitization of arterial blood pressure (ABP) to dietary salt in the −/− mice is associated with failure to downregulate plasma renin activity. To further characterize the role and mechanism of ANG II in the sensitization of ABP to salt in the ANP “knockout” mice, we measured ABP, heart rate (HR), and plasma catecholamine and aldosterone concentrations in −/− and +/+ mice maintained on HS for 4 wk and treated with daily injections of AT1 receptor antagonist DuP-753 (losartan) or distilled water (control). Daily food and water intake and fluid and electrolyte excretion were also measured during the first and last weeks of the dietary regimen. Cumulative urinary excretion of fluid and electrolytes did not differ significantly between genotypes and was not altered by chronic treatment with losartan. Basal ABP and HR were significantly elevated in control −/− mice compared with control +/+ mice. Losartan did not affect ABP or HR in +/+ mice, but reduced ABP and HR in the −/− mice to the levels in the +/+ mice. Total plasma catecholamine was elevated by approximately ten-fold in control −/− mice compared with control +/+ mice. Losartan reduced plasma catecholamine concentration significantly in −/− mice and abrogated the difference in plasma catecholamine between −/− and +/+ mice on HS diet. Plasma aldosterone did not differ significantly between genotypes and was not altered by losartan. We conclude that salt sensitivity of ABP in ANP knockout mice is mediated, at least in part, by a synergistic interaction between ANG II and sympathetic nerve activity.

scholarly journals Crucial role of Rho-nuclear factor-κB axis in angiotensin II-induced renal injury

2007 ◽  
Vol 293 (1) ◽  
pp. F100-F109 ◽  
Author(s):  
Yuri Ozawa ◽  
Hiroyuki Kobori
Keyword(s):  
Renal Injury ◽  
Kinase Inhibitor ◽  
Urinary Albumin Excretion ◽  
Rho Kinase ◽  
Urinary Albumin ◽  
Ang Ii ◽  
Kinase Activation ◽  
Protein Excretion ◽  
Rho Kinase Inhibitor ◽  
Tgf Β1

This study was performed to determine the effectiveness of the Rho kinase inhibitor and NF-κB inhibitor in renal injury of ANG II-infused hypertensive rats. Male Sprague-Dawley rats, maintained on a normal diet, received either a sham operation ( n = 7) or continuous ANG II infusion (120 ng/min) subcutaneously via minipumps. The ANG II-infused rats were further subdivided into three subgroups ( n = 7 each) to receive one of the following treatments during the entire period: vehicle, Rho kinase inhibitor (fasudil; 3 mg·kg−1·day−1 ip), or NF-κB inhibitor (parthenolide; 1 mg·kg−1·day−1 ip). After 12 days of ANG II infusion, systolic blood pressure (BP; 208 ± 7 vs. 136 ± 3 mmHg), Rho kinase activity, NF-κB activity, renal ANG II contents (160 ± 25 vs. 84 ± 14 pg/g), monocytic chemotactic protein (MCP) 1 mRNA, interstitial macrophage infiltration, transforming growth factor-β1 (TGF-β1) mRNA, interstitial collagen-positive area, urinary protein excretion (43 ± 6 vs. 11 ± 2 mg/day), and urinary albumin excretion were significantly enhanced compared with the Sham group. While fasudil or parthenolide did not alter systolic BP (222 ± and 190 ± 21, respectively), both treatments completely blocked ANG II-induced enhancement of NF-κB activity, renal ANG II contents (103 ± 11 and 116 ± 21 pg/g, respectively), MCP1 mRNA, interstitial macrophage infiltration, TGF-β1 mRNA, interstitial collagen-positive area, urinary protein excretion (28 ± 6 and 23 ± 3 mg/day, respectively), and urinary albumin excretion. Importantly, parthenolide did not alter ANG II-induced Rho kinase activation although fasudil abolished ANG II-induced Rho kinase activation. These data indicate that the Rho-NF-κB axis plays crucial roles in the development of ANG IIinduced renal injury independently from BP regulation.

Abstract 106: Signaling Mechanisms Affecting Nitric Oxide Production in Glomerular Podocytes

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Oleg Palygin ◽  
Daria V Ilatovskaya ◽  
Vladislav Levchenko ◽  
Bradley T Endres ◽  
Aron M Geurts ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Kidney Injury ◽  
No Production ◽  
Ang Ii ◽  
Paracrine Factors ◽  
Low Salt ◽  
Potent Vasodilator ◽  
No Signaling ◽  
Glomerular Ultrafiltration ◽  
Salt Sensitive Hypertension

While Nitric Oxide (NO), a potent vasodilator and vital signaling molecule, has been shown to contribute to the regulation of glomerular ultrafiltration, its role in podocytes during the pathogenesis of salt-sensitive hypertension has not yet been thoroughly examined. Recent studies have demonstrated that the deficiency of eNOS (the enzyme responsible for synthesizing NO) exacerbates renal injury and accelerates development of proteinuria and glomerulosclerosis. Considering this, we hypothesized that the podocytes of hypertensive animals would exhibit reduced NO production in response to various paracrine factors and this directly contributes to proteinuria. To test this, we isolated glomeruli from the kidneys of Dahl salt-sensitive (SS) rats fed either a high salt (HS; 4% NaCl, 3 weeks) or low salt (LS; 0.4% NaCl) diet and loaded podocytes with a combination of NO and Ca 2+ ionophores (DAF-FM and Fura Red, respectively). Changes in fluorescence were observed with the use of confocal microscopy in response to adenosine triphosphate (ATP), angiotensin II (Ang II), and H 2 O 2 . Application of Ang II or H 2 O 2 resulted in activation of both NO and [Ca 2+ ] i ; fluorescent transients which were significantly elevated in the soma and foot processes of podocytes of LS fed rats. In contrast, ATP specifically activated only changes in [Ca 2+ ] i , but did not have any effects on NO production. Ang II treatment also caused hypertrophy of the podocytes, whereas ATP had no effect on cell volume (41.1±7.7 vs. 0.1±3.6% increase for Ang II and ATP, respectively; P <0.05). Collectively, our results show that in contrast to [Ca 2+ ] i , which is modulated by all studied paracrine molecules, NO is produced by podocytes only in response to Ang II and H 2 O 2 , but not ATP. SS rats fed a HS diet for 3 weeks demonstrated impaired NO production; the response to Ang II or H 2 O 2 on HS contained only 23.7±6.6 and 43.4±28.4% of total effects on LS, respectively ( P <0.05). Therefore, when fed a HS diet, SS podocytes had an impaired NO response to Ang II or oxidative stress, suggesting that NO signaling is dysfunctional and likely contributes to the development of kidney injury.

Abstract 1170: SHP2-dependent Dephosphorylation of p190A Rho GAP Induces RhoA Activation by Angiotensin II in Vascular Smooth Muscle Cells

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Malvyne Rolli-Derkinderen ◽  
Jérémy Brégeon ◽  
Sarah J Parsons ◽  
Pierre Pacaud ◽  
Gervaise Loirand
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Kinase Activity ◽  
Rho Kinase ◽  
Ang Ii ◽  
Rhoa Activation ◽  
Kinase Pathway

Angiotensin II (Ang II) is a major regulator of blood pressure, that essentially acts through activation of Ang II type 1 receptor (AT1R) of vascular smooth muscle cells (VSMC). AT1R receptor activates numerous intracellular signaling pathways, including the small G protein RhoA known to control VSMC proliferation, migration, differentiation and contraction. Nevertheless, the mechanisms leading to RhoA activation by AT1R are unknown. RhoA activation can result from activation of RhoA exchange factor, that replaces bound GDP by GTP and/or inhibition of Rho GTPase-activating-protein (GAP) that hydrolyzes GTP to GDP. Here we assess the involvement of the p190A Rho GAP in RhoA activation induced by Ang II. The introduction of small interfering RNA (siRNA) targeting p190A in VSMC from rat aorta increased basal RhoA-Rho kinase pathway activity (790 ± 11% of control, n = 3). Moreover p190A-siRNA abolished the early activation of RhoA-Rho kinase pathway induced after 5 min of AngII (0.1 μM) stimulation but not the delayed RhoA activation induced after 60 min. We then measured p190A tyrosine phosphorylation known to reflect its activity. In resting VSMC, p190A was basally phosphorylated. In the presence of the AT2R inhibitor PD123319 (1 μM), activation of AT1R induced p190A dephosphorylation that was maximal at 5 min of Ang II stimulation (26 ± 5% of control, n = 4). The activation of AT2R by Ang II in the presence of losartan (1 μM) had no effect, neither on RhoA activation nor on p190A phosphorylation. Expression of a p190A phosphomimetic mutant decreased the basal activity of RhoA-Rho kinase pathway. In contrast expression of catalytically inactive or phosphoresistant p190A mutants increased the basal activity of RhoA-Rho kinase pathway and inhibited RhoA activation by Ang II. Moreover, using siRNA, we show that the tyrosine phosphatase SHP2, known to be activated by AT1R stimulation, was necessary for Ang II-mediated p190A dephosphorylation and RhoA activation. Our work demonstrates that RhoA/Rho kinase activity is controlled by the p190A Rho GAP in VSMC. Activity of p190A is basally high and maintains a low level of RhoA-Rho kinase activity in resting VSMC. Dephosphorylation of p190A through SHP2-dependent process is required for AT1R-induced RhoA activation.

scholarly journals Role of Rho in Salt-Sensitive Hypertension

2021 ◽  
Vol 22 (6) ◽  
pp. 2958
Author(s):  
Wakako Kawarazaki ◽  
Toshiro Fujita
Keyword(s):  
Intracellular Signaling ◽  
Salt Intake ◽  
Rho Kinase ◽  
Renin Angiotensin System ◽  
High Salt ◽  
No Production ◽  
Nucleotide Exchange ◽  
High Salt Intake ◽  
Guanosine Triphosphatase ◽  
Salt Sensitive Hypertension

A high amount of salt in the diet increases blood pressure (BP) and leads to salt-sensitive hypertension in individuals with impaired renal sodium excretion. Small guanosine triphosphatase (GTP)ase Rho and Rac, activated by salt intake, play important roles in the pathogenesis of salt-sensitive hypertension as key switches of intracellular signaling. Focusing on Rho, high salt intake in the central nervous system increases sodium concentrations of cerebrospinal fluid in salt-sensitive subjects via Rho/Rho kinase and renin-angiotensin system activation and causes increased brain salt sensitivity and sympathetic nerve outflow in BP control centers. In vascular smooth muscle cells, Rho-guanine nucleotide exchange factors and Rho determine sensitivity to vasoconstrictors such as angiotensin II (Ang II), and facilitate vasoconstriction via G-protein and Wnt pathways, leading to increased vascular resistance, including in the renal arteries, in salt-sensitive subjects with high salt intake. In the vascular endothelium, Rho/Rho kinase inhibits nitric oxide (NO) production and function, and high salt amounts further augment Rho activity via asymmetric dimethylarginine, an endogenous inhibitor of NO synthetase, causing aberrant relaxation and increased vascular tone. Rho-associated mechanisms are deeply involved in the development of salt-sensitive hypertension, and their further elucidation can help in developing effective protection and new therapies.

scholarly journals Angiotensin II-induced vascular endothelial dysfunction through RhoA/Rho kinase/p38 mitogen-activated protein kinase/arginase pathway

2011 ◽  
Vol 300 (5) ◽  
pp. C1181-C1192 ◽  
Author(s):  
Alia Shatanawi ◽  
Maritza J. Romero ◽  
Jennifer A. Iddings ◽  
Surabhi Chandra ◽  
Nagavedi S. Umapathy ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
P38 Mapk ◽  
Gene Knockout ◽  
Rho Kinase ◽  
Arginase Activity ◽  
No Production ◽  
Vascular Endothelial ◽  
Ang Ii ◽  
Vascular Endothelial Dysfunction

Enhanced vascular arginase activity impairs endothelium-dependent vasorelaxation by decreasing l-arginine availability to endothelial nitric oxide (NO) synthase, thereby reducing NO production. Elevated angiotensin II (ANG II) is a key component of endothelial dysfunction in many cardiovascular diseases and has been linked to elevated arginase activity. We determined signaling mechanisms by which ANG II increases endothelial arginase function. Results show that ANG II (0.1 μM, 24 h) elevates arginase activity and arginase I expression in bovine aortic endothelial cells (BAECs) and decreases NO production. These effects are prevented by the arginase inhibitor BEC (100 μM). Blockade of ANG II AT1 receptors or transfection with small interfering RNA (siRNA) for Gα12 and Gα13 also prevents ANG II-induced elevation of arginase activity, but siRNA for Gαq does not. ANG II also elevates active RhoA levels and induces phosphorylation of p38 MAPK. Inhibitors of RhoA activation (simvastatin, 0.1 μM) or Rho kinase (ROCK) (Y-27632, 10 μM; H1152, 0.5 μM) block both ANG II-induced elevation of arginase activity and phosphorylation of p38 MAPK. Furthermore, pretreatment of BAECs with p38 inhibitor SB-202190 (2 μM) or transfection with p38 MAPK siRNA prevents ANG II-induced increased arginase activity/expression and maintains NO production. Additionally, inhibitors of p38 MAPK (SB-203580, 5 μg·kg−1·day−1) or arginase (ABH, 8 mg·kg−1·day−1) or arginase gene knockout in mice prevents ANG II-induced vascular endothelial dysfunction and associated enhancement of arginase. These results indicate that ANG II increases endothelial arginase activity/expression through Gα12/13 G proteins coupled to AT1 receptors and subsequent activation of RhoA/ROCK/p38 MAPK pathways leading to endothelial dysfunction.

Mechanical Stress Induces Osteopontin via ATP/P2Y1 in Periodontal Cells

2008 ◽  
Vol 87 (6) ◽  
pp. 564-568 ◽  
Author(s):  
S. Wongkhantee ◽  
T. Yongchaitrakul ◽  
P. Pavasant
Keyword(s):  
Mechanical Stress ◽  
Alveolar Bone ◽  
Kinase Inhibitor ◽  
Inductive Effect ◽  
Rho Kinase ◽  
Chain Reaction ◽  
Kinase Activation ◽  
Rho Kinase Inhibitor ◽  
Polymerase Chain ◽  
Kinase Pathway

Our previous study showed that mechanical stress induced the expression of osteopontin (OPN) in human periodontal ligament (HPDL) cells through the Rho kinase pathway. The increase of OPN expression via Rho kinase has been demonstrated to be triggered by nucleotide. Therefore, we hypothesized that nucleotides, particularly adenosine triphosphate (ATP), participated in the stress-induced OPN expression in HPDL cells. In the present study, the roles of ATP and P2Y1 purinoceptor were examined. Reverse-transcription polymerase chain-reaction and Western blot analysis revealed that the stress-induced ATP exerted its stimulatory effect on OPN expression. The inductive effect was attenuated by apyrase and completely inhibited by the Rho kinase inhibitor, as well as by the P2Y1 antagonist. We here propose that stress induces release of ATP, which in turn mediates Rho kinase activation through the P2Y1 receptor, resulting in the up-regulation of OPN. Stress-induced ATP could play a significant role in alveolar bone resorption.

scholarly journals Angiotensin II-Induced Vasoconstriction via Rho Kinase Activation in Pressure-Overloaded Rat Thoracic Aortas

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1076
Author(s):  
Yuka Terada ◽  
Katsutoshi Yayama
Keyword(s):  
Angiotensin Ii ◽  
Rho Kinase ◽  
Growth Factor Receptor ◽  
Janus Kinase ◽  
Ang Ii ◽  
Kinase Activation ◽  
Jak2 Inhibitor ◽  
Protein Levels ◽  
Extracellular Signal ◽  
Male Wistar Rats

Angiotensin II (Ang II) induces vasoconstriction through myosin light chain (MLC) kinase activation and MLC phosphatase inactivation via phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) by Rho kinase. However, the detailed mechanism underlying Rho kinase activation by Ang II is still unknown. We investigated the mechanism of Ang II-induced vasoconstriction mediated by Rho kinase in pressure-overloaded rat thoracic aortas. Pressure-overloaded rats were produced by coarctation of the suprarenal abdominal aorta in four-week-old male Wistar rats. The contractile response to Ang II was significantly enhanced in the pressure-overloaded rats. Ang II-induced vasoconstriction was attenuated by inhibitors of Rho kinase, extracellular signal-regulated kinase 1 and 2 (Erk1/2), and epidermal growth factor receptor (EGFR) in both the sham-operated and pressure-overloaded rats. The Ang II-induced vasoconstriction was attenuated by a Janus kinase 2 (JAK2) inhibitor in only the pressure-overloaded rats. The protein levels of MYPT1 and JAK2 increased only in the pressure-overloaded rat thoracic aortas. These results suggested that Ang II-induced contraction is mediated by Rho kinase activation via EGFR, Erk1/2, and JAK2 in pressure-overloaded rat thoracic aortas. Moreover, Ang II-induced contraction was enhanced in pressure-overloaded rats probably because the protein levels of MYPT1 and JAK2 increased in the thoracic aortas.

Role of superoxide and angiotensin II suppression in salt-induced changes in endothelial Ca2+ signaling and NO production in rat aorta

2006 ◽  
Vol 291 (2) ◽  
pp. H929-H938 ◽  
Author(s):  
Jiaxuan Zhu ◽  
Ines Drenjancevic-Peric ◽  
Scott McEwen ◽  
Jill Friesema ◽  
Danielle Schulta ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Rat Aorta ◽  
No Production ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Dietary Salt ◽  
Aortic Endothelial Cells ◽  
No Release ◽  
Intracellular Ca

Male Sprague-Dawley rats were maintained on a low-salt (LS) diet (0.4% NaCl) or changed to a high-salt (HS) diet (4% NaCl) for 3 days. Increases in intracellular Ca2+ ([Ca2+]i) in response to methacholine (10 μM) and histamine (10 μM) were significantly attenuated in aortic endothelial cells from rats fed a HS diet, whereas thapsigargin (10 μM)-induced increases in [Ca2+]i were unaffected. Methacholine-induced nitric oxide (NO) production was eliminated in endothelial cells of aortas from rats fed a HS diet. Low-dose ANG II infusion (5 ng·kg−1·min−1 iv) for 3 days prevented impaired [Ca2+]i signaling response to methacholine and histamine and restored methacholine-induced NO production in aortas from rats on a HS diet. Adding Tempol (500 μM) to the tissue bath to scavenge superoxide anions increased NO release and caused Nω-nitro-l-arginine methyl ester-sensitive vascular relaxation in aortas from rats fed a HS diet but had no effect on methacholine-induced Ca2+ responses. Chronic treatment with Tempol (1 mM) in the drinking water restored NO release, augmented vessel relaxation, and increased methacholine-induced Ca2+ responses significantly in aortas from rats on a HS diet but not in aortas from rats on a LS diet. These findings suggest that 1) agonist-induced Ca2+ responses and NO levels are reduced in aortas of rats on a HS diet; 2) increased vascular superoxide levels contribute to NO destruction, and, eventually, to impaired Ca2+ signaling in the vascular endothelial cells; and 3) reduced circulating ANG II levels during elevated dietary salt lead to elevated superoxide levels, impaired endothelial Ca2+ signaling, and reduced NO production in the endothelium.

RhoA guanine exchange factor expression profile in arteries: evidence for a Rho kinase-dependent negative feedback in angiotensin II-dependent hypertension

2012 ◽  
Vol 302 (9) ◽  
pp. C1394-C1404 ◽  
Author(s):  
Chrystelle Cario-Toumaniantz ◽  
David Ferland-McCollough ◽  
Gilliane Chadeuf ◽  
Gilles Toumaniantz ◽  
Marianne Rodriguez ◽  
...  
Keyword(s):  
Expression Profile ◽  
Negative Feedback ◽  
Rho Kinase ◽  
Mesenteric Arteries ◽  
Ang Ii ◽  
Rho Proteins ◽  
Protein Activity ◽  
Common Component ◽  
Kinase Activation

Sustained overactivation of RhoA is a common component for the pathogenesis of several cardiovascular disorders, including hypertension. Although activity of Rho proteins depends on Rho exchange factors (Rho-GEFs), the identity of Rho-GEFs expressed in vascular smooth muscle cells (VSMC) and participating in the control of Rho protein activity and Rho-dependent functions remains unknown. To address this question, we analyzed by quantitative RT-PCR the expression profile of 28 RhoA-GEFs in arteries of normotensive (saline-treated) and hypertensive (ANG II-treated) rats. Sixteen RhoA-GEFs were downregulated in mesenteric arteries of hypertensive rats, among which nine are also downregulated in cultured VSMC stimulated by ANG II (100 nM, 48 h), suggesting a direct effect of ANG II. Inhibition of type 1 ANG II receptors (losartan, 1 μM) or Rho kinase (fasudil, 10 μM) prevented ANG II-induced RhoA-GEF downregulation. Functionally, ANG II-induced downregulation of RhoA-GEFs is associated with decreased Rho kinase activation in response to endothelin-1, norepinephrine, and U-46619. This work thus identifies a group of RhoA-GEFs that controls RhoA and RhoA-dependent functions in VSMC, and a negative feedback of RhoA/Rho kinase activity on the expression of these RhoA-GEFs that may play an adaptative role to limit RhoA/Rho kinase activation.

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