Regulator of G-Protein Signaling 5 Prevents Smooth Muscle Cell Proliferation and Attenuates Neointima Formation

Abstract

Objective-Regulator of G-protein signaling 5 (RGS5) is abundantly expressed in vascular smooth muscle cells (SMCs) and inhibits G-protein signaling by enhancing the guanosine triphosphate-hydrolyzing activity of Gα-subunits. In the present study, we investigated the effects of RGS5 on vascular SMC function in vitro and neointima formation after wire-induced injury in mice and determined the underlying mechanisms. Approach and Results-We found a robust expression of RGS5 in native arteries of C57BL/6 mice and a highly significant downregulation within neointimal lesions 10 and 21 days after vascular injury as assessed by quantitative polymerase chain reaction, immunoblotting, and immunohistochemistry. In vitro, RGS5 was found significantly downregulated after mitogenic stimulation of human coronary artery SMCs. To restore RGS5 levels, SMCs were transduced with adenoviral vectors encoding wild-type RGS5 or a nondegradable mutant. RGS5-WT and, even more prominently, the C2A-RGS5 mutant prevented SMC proliferation and migration. In contrast, the siRNA-mediated knockdown of RGS5 significantly augmented SMC proliferation. Following overexpression of RGS5, fluorescence-activated cell sorting analysis of propidium iodide-stained cells indicated cell cycle arrest in G0/G1 phase. Mechanistically, inhibition of the phosphorylation of the extracellular signal-regulated kinase 1/2 and mitogen-activated protein kinase downstream signaling was shown to be responsible for the anti-proliferative effect of RGS5. Following wire-induced injury of the femoral artery in C57BL/6 mice, adenoviral-mediated overexpression of RGS5-WT or C2A-RGS5 significantly reduced SMC proliferation and neointima formation in vivo. Conclusions-Downregulation of RGS5 is an important prerequisite for SMC proliferation in vitro and in vivo.Therefore, reconstitution of RGS5 levels represents a promising therapeutic option to prevent vascular remodeling processes.

Transcriptome analyses of ovarian stroma: tunica albuginea, interstitium and theca interna

“…Regulator of G-protein signalling 5 (RGS5), a member of the family of RGS molecules that regulate the signal transduction of G-protein-coupled receptors (GPCRs) and G-proteins, is expressed by pericytes and vascular smooth muscle cells (Bondjers et al 2003, Cho et al 2003, Berger et al 2005. RGS5 has been found to downregulate proliferation of vascular smooth muscle cells in vivo and in vitro (Daniel et al 2016). Induced expression of RGS5 significantly reduced cell proliferation of ovarian cancer tumour cells in vitro and increased the vascular density in tumours in vivo (Altman et al 2012).…”

Cells of the adult human heart

“…Vascular SMCs that express MYH11 split into two populations. SMC1_basic cells express transcripts that indicate immaturity, including the stem-cell marker LGR6 37 and proliferation-associated RGS5 38 . SMC2_art cells express considerably higher levels of CNN1 , ACTA2 and TAGLN , indicating arterial origin, whereas SMC1_basic cells may be venous-derived 39 (Extended Data Fig.…”

Ultrahigh-Resolution Optical Coherence Elastography Images Cellular-Scale Stiffness of Mouse Aorta

“…G-protein signaling is an important process in cardiovascular function (39)(40)(41)(42). RGS5 protein is predominantly expressed in arterial vascular smooth muscle cells (43,44) and has recently emerged as a critical regulator of cardiovascular remodeling processes (39,45,46). With elastography, we observe the cellular-scale organization of the aorta and, in some cases, the individual mechanics of elastic lamellae and vascular smooth muscle.…”