RGS 5 promotes arterial growth during arteriogenesis

Abstract

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 ( RGS 5) is increased in vascular smooth muscle cells ( SMC s) of remodelling collateral arterioles. RGS 5 terminates G ‐protein‐coupled signalling cascades which control contractile responses of SMC s. Consequently, overexpression of RGS 5 blunted Gα q/11 ‐mediated mobilization of intracellular calcium, thereby facilitating Gα 12/13 ‐mediated RhoA signalling which is crucial for arteriogenesis. Knockdown of RGS 5 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 RGS 5‐deficient mice after the onset of arteriogenesis. Collectively, these findings establish RGS 5 as a novel determinant of arteriogenesis which shifts G‐protein signalling from Gα q/11 ‐mediated calcium‐dependent contraction towards Gα 12/13 ‐mediated Rho kinase‐dependent SMC activation. image 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 RGS 5 is critical for arteriogenesis and a suitable therapeutic target. RGS 5 is expressed in vascular smooth muscle cells of growing collateral arterioles during arteriogenesis. RGS 5 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 RGS 5, while Gα12/13‐mediated RhoA activation is promoted. Arteriogenic collateral growth is reduced by almost 90% in RGS 5‐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 RGS 5 (e.g. neointima formation is reduced by almost 70% in RGS 5‐deficient mice).