Arteriogenesis—the growth of collateral arterioles—partially compensates for the progressive occlusion of large conductance arteries as it may occur as a consequence of coronary, cerebral or peripheral artery disease. Despite being clinically highly relevant, mechanisms driving this process remain elusive. In this context, our study revealed that abundance of regulator of G-protein signalling 5 (RGS5) is increased in vascular smooth muscle cells (SMCs) of remodelling collateral arterioles. RGS5 terminates G-protein-coupled signalling cascades which control contractile responses of SMCs. Consequently, overexpression of RGS5 blunted Gαq/11-mediated mobilization of intracellular calcium, thereby facilitating Gα12/13-mediated RhoA signalling which is crucial for arteriogenesis. Knockdown of RGS5 evoked opposite effects and thus strongly impaired collateral growth as evidenced by a blockade of RhoA activation, SMC proliferation and the inability of these cells to acquire an activated phenotype in RGS5-deficient mice after the onset of arteriogenesis. Collectively, these findings establish RGS5 as a novel determinant of arteriogenesis which shifts G-protein signalling from Gαq/11-mediated calcium-dependent contraction towards Gα12/13-mediated Rho kinase-dependent SMC activation.
While arteriogenesis can reduce the risk of mortality due to coronary artery disease, the molecular mechanism behind arterial remodelling remains unclear. This study shows that RGS5 is critical for arteriogenesis and a suitable therapeutic target.
- RGS5 is expressed in vascular smooth muscle cells of growing collateral arterioles during arteriogenesis.
- RGS5 protein abundance is increased in vascular smooth muscle cells upon prolonged stimulation with nitric oxide and biomechanical stretch—rate-limiting determinants of collateral growth.
- Gαq/11-mediated calcium-dependent smooth muscle cell contraction is limited by RGS5, while Gα12/13-mediated RhoA activation is promoted.
- Arteriogenic collateral growth is reduced by almost 90% in RGS5-deficient mice due to impaired RhoA and smooth muscle cell activation.
- Other vascular remodelling processes requiring the activation of vascular smooth muscle cells are limited by loss of RGS5 (e.g. neointima formation is reduced by almost 70% in RGS5-deficient mice).