G protein-coupled receptors (GPCRs) are major regulators of contractility of vascular smooth muscle cells (VSMCs) thereby controlling vascular tone, blood pressure and flow. GPCR signaling is modulated by the regulators of G protein signaling (RGS) which terminate G protein activation. Even though RGS5 is known to prevent Gα_q activation in arterial VSMCs, its role in maladaptive arterial remodeling remains unclear.

To this end, arteriogenesis - the flow and wall stress-induced growth of pre-existing collateral arterioles - was induced by ligating the femoral artery in the mouse hindlimb. Subsequent immunofluorescence analyses of remodeling arterioles revealed an increase in RGS5 abundance in medial VSMCs. In vitro studies with cultured human arterial VSMCs exposed to cyclic stretch thus mimicking elevated wall tension, led to an increase in RGS5 expression, confirming this biomechanical force as an important determinant of RGS5 activity. In line with its ability to inhibit Gα_q activation, over-expression of RGS5 in human arterial VSMCs prevented Ca²⁺-mediated constriction upon sphingosine-1-phosphate (S1P) stimulation. In contrast, S1P-stimulated isolated rgs5-deficient arteries showed enhanced contractility. Further experiments delineating the impact of RGS5 on the outcome of the VSMC response after S1P stimulation revealed a shift from Gα_q towards Gα_12/13-mediated RhoA activation and stress fiber formation. Moreover, the arteriolar remodeling process was disturbed in rgs5-deficient mice indicating this mechanism to be important for the onset of arteriogenic remodeling.

In summary, an increase in wall stress controls RGS5 expression which blunts Ca²⁺-mediated vasoconstriction leading to Gα_12/13-dependent RhoA activation. This appears to be highly critical for vascular remodeling.