Involvement of Rho GTPases and their regulators in the pathogenesis of hypertension

Loirand, Gervaise; Pacaud, Pierre

doi:10.4161/sgtp.28846

Cited by 55 publications

(54 citation statements)

References 90 publications

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“…Loss of IP 3 Rs in VSMCs significantly attenuated the elevation of blood pressure in a hypertensive state induced by chronic AngII infusion. It has been proposed that increased RhoA and Rock activities play a causative role in the pathogenesis of AngII-induced hypertension (27). We showed that loss of IP 3 Rs in VSMCs caused blunted MYPT1 phosphorylation in response to acute vasoconstrictive stimulation.…”

Section: +mentioning

confidence: 54%

“…MLC20 phosphorylation level is regulated by MLC kinase (MLCK) and phosphatase (MLCP), the latter consisting of a myosin-binding regulatory subunit (MYPT1), a catalytic subunit, and a 20-kDa subunit. Phosphorylation of MYPT1 decreases MLCP activity and therefore enhances MLC20 phosphorylation (27). Western blot analysis showed that expression of MLC20, MLCK, and MYPT1 in smTKO aortas is comparable to that of control aortas.…”

Section: Expression and Deletion Of Ipmentioning

confidence: 92%

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IP3 receptors regulate vascular smooth muscle contractility and hypertension

et al. 2016

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Section: +mentioning

confidence: 54%

Section: Expression and Deletion Of Ipmentioning

confidence: 92%

IP3 receptors regulate vascular smooth muscle contractility and hypertension

et al. 2016

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“…15 Other intracellular mechanisms favoring eNOS dysfunction include disruption of the interaction of the enzyme with caveolae, NFκB activation, suppression by transcription factor forkhead box O-1 of Krüppel-like factor-2 and increased endoplasmic reticulum stress. 15,126 In addition, eNOS dysfunction can be exacerbated by many genetic manipulations that include (1) deletion of bone morphogenetic protein type II receptors [receptors that activate PKA to cause eNOS phosphorylation at Ser1177; their mutation is associated with the development of pulmonary arterial hypertension]; (2) deletion of α-calcitonin gene-related peptide [neuropeptide that induces the expression of eNOS and causes its phosphorylation by activating PKA and AMPK]; (3) deletion of small GTPase Ras-related protein 1 134 impairing activation of integrins (eg, by shear stress) and the subsequent stimulation of the focal adhesion kinase/PI3K/Akt pathway; (4) endothelium-specific deletion of liver kinase B1 impairing AMPK activation; (5) reduction in the level of S100A1, enhancing PKC activity with increased eNOS phosphorylation at Thr495 and reducing that of the PI3K/Akt and the ERK1/2 pathways with decreased eNOS phosphorylation at Ser1177; and (6) expression of myristoylation-deficient eNOS preventing the membrane targeting and thiopalmitoylation of the enzyme ( Figure 6). 15,51 Experimentally, the occurrence of dysfunction of the NO pathway can be prevented/alleviated by (1) elevation of the circulating levels of adiponectin; (2) activation of angiotensin-converting enzyme 2 or administration of angiotensin [1][2][3][4][5][6][7] ; (3) stimulation of the production or long-term administration of erythropoietin 112 enhancing the activation of Akt; (4) administration of stable melanocortin analogs, cannabidiol, 135 and dietary capsaicin, which activate TRPV1 channels of the endothelial cell membrane leading to calcium influx and calcium-dependent stimulation of calcium/calmodulin-dependent PK II phosphorylating eNOS at Ser1177; (5) administration of AMPK-activators such as AICAR; and (6) upregulation of micro-RNA-181b 136 (present in endothelial cells of adipose tissue after high-fat diet; which suppresses the expression of the leucine-rich repeat PP-2 that dephosphorylates and inactivates Akt).…”

Section: Reduced Protein Dimerizationmentioning

confidence: 99%

Thirty Years of Saying NO

Vanhoutte

Zhao

et al. 2016

Circulation Research

330

156

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T he historical demonstration by Furchgott and Zawadzki 1 that removal of the endothelium abrogates the in vitro vasodilator effect of acetylcholine has led to the identification 30 years ago of nitric oxide (NO) as a major endogenous local regulator of vascular tone. [2][3][4][5][6][7][8][9][10] When the ability of endothelial cells to produce NO is blunted, the ensuing vascular dysfunction sets the stage for the occurrence of cardiovascular disease in general, and atherosclerosis in particular. [11][12][13][14][15] This review focuses, stepby-step, on the bioavailability (production, action, and disposition) of endothelium-derived NO as local regulator of vascular tone in health and disease. Obviously, there is much more than NO in the control of the degree of contraction of underlying vascular smooth muscle cells exerted by the endothelial cells. Indeed, they generate also prostacyclin and hyperpolarizing signals (initiating endothelium-dependent hyperpolarization [EDH] and thus relaxation) and produce vasoconstrictor mediators (endothelium-derived contracting factors and the peptide endothelin-1); those have been discussed elsewhere in detail. 15-22 Endothelial Sources of NO NO SynthaseThree NO synthase (NOS) isozymes, which are encoded by different genes, catalyze the production of NO from l-arginine: neuronal NOS (or NOS-1), cytokine-inducible NOS (iNOS or NOS-2), and endothelial NOS (eNOS or NOS-3).6,23-25 Although iNOS can be induced (by lipopolysaccharides and inflammatory cytokines) and neuronal NOS can be present in the blood vessel

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“…NOX1 activation is known to enhance calcium (Ca 21 ) mobilization in VSMCs, which does not affect VSMC migration alone (Rossi et al, 2009;Li et al, 2011;Zimmerman et al, 2011;Duran-Prado et al, 2013). VSMC contraction is highly Ca 21 -dependent, and the role of Rho GTPases therein is extensively discussed in a recent review by Loirand and Pacaud (2014). Whereas the role of GTPase RhoA in VSMC contraction is clear, inducing vasoconstriction upon activation resulting from the rise of cytosolic Ca 21 , the role of Rac1 is still quite obscure.…”

Section: Vascular Smooth Muscle Cellsmentioning

confidence: 99%

“…This inactivation prolongs the phosphorylated state of MLC and thus increased contractility of VSMC. Loirand and Pacaud (2014) extensively describe Rac1 activation in VSMC as not that straightforward. Collectively, the context of Rac1 activation seems to determine if Rac1 activation leads to vasoconstriction or vasodilation.…”

Section: Vascular Smooth Muscle Cellsmentioning

confidence: 99%

The Ins and Outs of Small GTPase Rac1 in the Vasculature

Marinković

Heemskerk

Buul

et al. 2015

J Pharmacol Exp Ther

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The Rho family of small GTPases forms a 20-member family within the Ras superfamily of GTP-dependent enzymes that are activated by a variety of extracellular signals. The most well known Rho family members are RhoA (Ras homolog gene family, member A), Cdc42 (cell division control protein 42), and Rac1 (Ras-related C3 botulinum toxin substrate 1), which affect intracellular signaling pathways that regulate a plethora of critical cellular functions, such as oxidative stress, cellular contacts, migration, and proliferation. In this review, we describe the current knowledge on the role of GTPase Rac1 in the vasculature. Whereas most recent reviews focus on the role of vascular Rac1 in endothelial cells, in the present review we also highlight the functional involvement of Rac1 in other vascular cells types, namely, smooth muscle cells present in the media and fibroblasts located in the adventitia of the vessel wall. Collectively, this overview shows that Rac1 activity is involved in various functions within one cell type at distinct locations within the cell, and that there are overlapping but also cell type-specific functions in the vasculature. Chronically enhanced Rac1 activity seems to contribute to vascular pathology; however, Rac1 is essential to vascular homeostasis, which makes Rac1 inhibition as a therapeutic option a delicate balancing act.

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Involvement of Rho GTPases and their regulators in the pathogenesis of hypertension

Cited by 55 publications

References 90 publications

IP3 receptors regulate vascular smooth muscle contractility and hypertension

IP3 receptors regulate vascular smooth muscle contractility and hypertension

Thirty Years of Saying NO

The Ins and Outs of Small GTPase Rac1 in the Vasculature

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