Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, C100

Oral Communications

Wall stress-mediated RGS5 expression in vascular smooth muscle cells controls arterial remodeling during hypertension

C. Arnold1, E. Demirel1, A. Feldner1, G. Genové2, H. Zhang3, C. Sticht4, T. Wieland5, M. Hecker1, S. Heximer3, T. Korff1

1. Institute of Physiology and Pathophysiology, Department of Cardiovascular Physiology, Heidelberg University, Heidelberg, Germany. 2. Integrated CardioMetabolic Centre, Karolinska Institute, Huddinge, Sweden. 3. Department of Physiology, Heart & Stroke Richard Lewar Centre of Excellence for Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada. 4. Center of Medical Research, Bioinformatic and Statistic, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. 5. Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.


During the onset of hypertension, vascular smooth muscle cells (VSMCs) are exposed to an increase in wall stress which translates to biomechanical stretch that induces a compensatory thickening of the vascular wall. Eventually, this leads to arterial stiffening which poses as a main risk factor for cardiovascular diseases including myocardial infarction and stroke. In this context, G-protein signaling has been reported to control blood pressure and VSMC activation. So far, it remains unclear how G-protein activity is controlled in VSMCs under these conditions. To this end, we investigated the impact of the regulator of G-protein signaling 5 (RGS5), an endogenous inhibitor of Gαq/11 and Gαi/o activity, on blood pressure and the VSMC phenotype during experimental hypertension in mice. To analyze the onset of hypertension, deoxycorticosterone acetate pellets (50 mg/pellet) were implanted subcutaneously for 10 days and the mice were fed 1 % sodium chloride in the drinking water. All results are expressed as mean ± S.D. and analyzed by one-way ANOVA. Loss of RGS5 in mice (RGS5-/-) did not affect baseline mean arterial pressure or the development of hypertension (WT 102±7.5 vs. RGS5-/- 106±3.8 mmHg, hypertension WT 117.7±5.5 vs. RGS5-/- 114.6±2.1 mmHg, n=5-6, not significant) but prevented hypertension-induced arterial remodeling, i.e. thickening of the vascular wall due to VSMC proliferation (PCNA-positive nuclei hypertension WT 53±11.2 vs. RGS5-/- 2±3.7, n=5, p<0.01). Under these conditions, RGS5-/- VSMCs maintained a contractile phenotype as evidenced by the presence of α-smooth muscle actin (grey intensity hypertension WT 1292.03±143.1 vs. RGS5-/- 1605.5±473.1, n=5, p<0.05) and smooth muscle-myosin heavy chain (relative grey intensity hypertension WT 0.5±0.4 vs. RGS5-/- 1.3±0.4, n=8-11, p<0.05). Mechanistically, exposing isolated arteries to hypertensive pressure levels or VSMCs to biomechanical stretch was sufficient to increase RGS5 expression (arteries 1.9 fold±1.3, n=13, VSMCs 3.2 fold±1.1, n=3, p<0.05). Further, the absence of RGS5 severely impaired RhoA activity - a key protein that controls arterial remodeling in mice and humans - in arteries of hypertensive mice (WT 1.5±0.3 vs. RGS5-/- 1.1±0.2, n=4, p<0.05) as well as in stretch-exposed VSMCs (WT 1.1±0.6 vs. RGS5-/- 0.6±0.08, n=3, p<0.05). However, stretch-induced RhoA activity could be rescued by PKC inhibition that mimics RGS5-mediated termination of Gαq/11 signaling (solvent 1.2±0.3 vs. PKC inhibitor 2.2±0.7, n=5, p<0.05). Collectively, our findings identify RGS5 as a mechanoresponsive protein and demonstrate that RhoA activation depends on the restriction of G-protein activity. This mechanism seems to be a prerequisite for (stretch-dependent) vascular remodeling processes and might serve as a therapeutic target to combat hypertension-induced detrimental vascular changes.

Where applicable, experiments conform with Society ethical requirements