RGS5 Attenuates Baseline Activity of ERK1/2 and Promotes Growth Arrest of Vascular Smooth Muscle Cells

The regulator of G-protein signaling 5 (RGS5) acts as an inhibitor of Gαq/11 and Gαi/o activity in vascular smooth muscle cells (VSMCs), which regulate arterial tone and blood pressure. While RGS5 has been described as a crucial determinant regulating the VSMC responses during various vascular remodeling processes, its regulatory features in resting VSMCs and its impact on their phenotype are still under debate and were subject of this study. While Rgs5 shows a variable expression in mouse arteries, neither global nor SMC-specific genetic ablation of Rgs5 affected the baseline blood pressure yet elevated the phosphorylation level of the MAP kinase ERK1/2. Comparable results were obtained with 3D cultured resting VSMCs. In contrast, overexpression of RGS5 in 2D-cultured proliferating VSMCs promoted their resting state as evidenced by microarray-based expression profiling and attenuated the activity of Akt- and MAP kinase-related signaling cascades. Moreover, RGS5 overexpression attenuated ERK1/2 phosphorylation, VSMC proliferation, and migration, which was mimicked by selectively inhibiting Gαi/o but not Gαq/11 activity. Collectively, the heterogeneous expression of Rgs5 suggests arterial blood vessel type-specific functions in mouse VSMCs. This comprises inhibition of acute agonist-induced Gαq/11/calcium release as well as the support of a resting VSMC phenotype with low ERK1/2 activity by suppressing the activity of Gαi/o.

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Abstract 524: Extracellular Guanosine Regulates Extracellular Adenosine Levels

Hypertension ◽

10.1161/hyp.60.suppl_1.a524 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Edwin K Jackson ◽

Delbert G Gillespie

Keyword(s):

Blood Pressure ◽

Endothelial Cells ◽

Smooth Muscle ◽

Coronary Artery ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Muscle Cells ◽

Extracellular Adenosine ◽

Arterial Blood

Extracellular adenosine modulates cardiovascular and renal function. While measuring extracellular purines in biological samples, we observed a correlation between levels of adenosine and guanosine. This observation led us to test the hypothesis that extracellular guanosine regulates extracellular adenosine levels in the cardiovascular and renal systems. Rat preglomerular vascular smooth muscle cells in culture were incubated with adenosine and/or guanosine. In the absence of added adenosine, exogenous guanosine (30 μmol/L) had little effect on extracellular adenosine levels, indicating that extracellular guanosine does not trigger the release or production of adenosine. Without added guanosine and 1 hour after adding 3 μmol/L of exogenous adenosine, extracellular adenosine levels were only 0.125 ± 0.020 μmol/L, indicating rapid disposition of extracellular adenosine by a monolayer of cells. In contrast, extracellular adenosine levels 1 hour after adding 3 μmol/L of adenosine plus guanosine (30 μmol/L) were 1.173 ± 0.061 μmol/L (9-fold higher; p<0.0001), indicating slow disposition of extracellular adenosine in the presence of extracellular guanosine. Extracellular guanosine impeded the disposition of extracellular adenosine not only in preglomerular vascular smooth muscle cells, but also in rat preglomerular vascular endothelial cells, mesangial cells, cardiac fibroblasts and kidney epithelial cells, as well as in human aortic vascular smooth muscle cells, coronary artery vascular smooth muscle cells and coronary artery endothelial cells. In rats, infusions of guanosine per se had little effect on cardiovascular/renal variables, yet markedly enhanced the effects of co-infusions of adenosine. For example, in control rats, adenosine (0.3 μmol/kg/min) only modestly decreased mean arterial blood pressure (from 114 ± 4 to 100 ± 4 mm Hg). In contrast, in guanosine-treated rats (10 μmol/kg/min), adenosine profoundly decreased blood pressure (from 109 ± 4 to 79 ± 3 mm Hg; p<0.0001 vs non-guanosine treated group). Conclusion: Extracellular guanosine powerfully regulates extracellular adenosine levels by altering adenosine disposition and this occurs in many, perhaps most, cell types in the cardiovascular system and kidneys.

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The vascular Ca2+-sensing receptor regulates blood vessel tone and blood pressure

AJP Cell Physiology ◽

10.1152/ajpcell.00248.2015 ◽

2016 ◽

Vol 310 (3) ◽

pp. C193-C204 ◽

Cited By ~ 38

Author(s):

M. Schepelmann ◽

P. L. Yarova ◽

I. Lopez-Fernandez ◽

T. S. Davies ◽

S. C. Brennan ◽

...

Keyword(s):

Blood Pressure ◽

Smooth Muscle ◽

Blood Vessel ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Active Phase ◽

Muscle Cells ◽

Extracellular Calcium ◽

Arterial Blood

The extracellular calcium-sensing receptor CaSR is expressed in blood vessels where its role is not completely understood. In this study, we tested the hypothesis that the CaSR expressed in vascular smooth muscle cells (VSMC) is directly involved in regulation of blood pressure and blood vessel tone. Mice with targeted CaSR gene ablation from vascular smooth muscle cells (VSMC) were generated by breeding exon 7 LoxP-CaSR mice with animals in which Cre recombinase is driven by a SM22α promoter (SM22α-Cre). Wire myography performed on Cre-negative [wild-type (WT)] and Cre-positive SM22αCaSRΔflox/Δflox [knockout (KO)] mice showed an endothelium-independent reduction in aorta and mesenteric artery contractility of KO compared with WT mice in response to KCl and to phenylephrine. Increasing extracellular calcium ion (Ca2+) concentrations (1–5 mM) evoked contraction in WT but only relaxation in KO aortas. Accordingly, diastolic and mean arterial blood pressures of KO animals were significantly reduced compared with WT, as measured by both tail cuff and radiotelemetry. This hypotension was mostly pronounced during the animals' active phase and was not rescued by either nitric oxide-synthase inhibition with nitro-l-arginine methyl ester or by a high-salt-supplemented diet. KO animals also exhibited cardiac remodeling, bradycardia, and reduced spontaneous activity in isolated hearts and cardiomyocyte-like cells. Our findings demonstrate a role for CaSR in the cardiovascular system and suggest that physiologically relevant changes in extracellular Ca2+ concentrations could contribute to setting blood vessel tone levels and heart rate by directly acting on the cardiovascular CaSR.

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