RGS5 promotes arterial growth during arteriogenesis

EMBO Mol Med. 2014 Aug;6(8):1075-89. doi: 10.15252/emmm.201403864.

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 (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.

Keywords: G‐protein; RGS5; arteriogenesis; remodelling; vascular smooth muscle cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arterioles / growth & development*
  • Cell Proliferation
  • GTP-Binding Protein alpha Subunits, G12-G13 / metabolism
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • Gene Knockdown Techniques
  • Mice
  • Mice, Knockout
  • Myocytes, Smooth Muscle / physiology
  • RGS Proteins / genetics
  • RGS Proteins / metabolism*
  • rhoA GTP-Binding Protein / metabolism

Substances

  • RGS Proteins
  • Rgs5 protein, mouse
  • GTP-Binding Protein alpha Subunits, G12-G13
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • rhoA GTP-Binding Protein