RGS5 Attenuates Baseline Activity of ERK1/2 and Promotes Growth Arrest of Vascular Smooth Muscle Cells

Abstract

The regulator of G-protein signaling 5 (RGS5) acts as an inhibitor of Gαq/11 and Gαi/o activity in vascular smooth muscle cells (VSMCs), which regulate arterial tone and blood pressure. While RGS5 has been described as a crucial determinant regulating the VSMC responses during various vascular remodeling processes, its regulatory features in resting VSMCs and its impact on their phenotype are still under debate and were subject of this study. While Rgs5 shows a variable expression in mouse arteries, neither global nor SMC-specific genetic ablation of Rgs5 affected the baseline blood pressure yet elevated the phosphorylation level of the MAP kinase ERK1/2. Comparable results were obtained with 3D cultured resting VSMCs. In contrast, overexpression of RGS5 in 2D-cultured proliferating VSMCs promoted their resting state as evidenced by microarray-based expression profiling and attenuated the activity of Akt- and MAP kinase-related signaling cascades. Moreover, RGS5 overexpression attenuated ERK1/2 phosphorylation, VSMC proliferation, and migration, which was mimicked by selectively inhibiting Gαi/o but not Gαq/11 activity. Collectively, the heterogeneous expression of Rgs5 suggests arterial blood vessel type-specific functions in mouse VSMCs. This comprises inhibition of acute agonist-induced Gαq/11/calcium release as well as the support of a resting VSMC phenotype with low ERK1/2 activity by suppressing the activity of Gαi/o.

Age-dependent RGS5 loss in pericytes induces cardiac dysfunction and fibrosis in the heart

“…Although RGS5 is also expressed in smooth muscle cells, no difference in blood systolic and diastolic pressure, and mean arterial pressure were observed in the global Rgs5 KO 59 and in smooth muscle cell specific Rgs5 knock-out mice 9 under baseline conditions. Furthermore, we detected difuse but not perivascular fibrosis in the Rgs5 ΔPC hearts.…”

“…Moreover, pro-inflammatory receptors like IL6R and IL7R are upregulated upon RGS5 knockdown ( Figure 7C ). RGS5 has been described as negative regulator of Gαq signalling 9,48 . To investigate whether RGS5 regulates GPCR signalling in pericytes, we measured the Gαq-dependent inositol-1-phosphate (IP1) production upon RGS5 knockdown.…”

“…Moreover, pro-inflammatory receptors like IL6R and IL7R are upregulated upon RGS5 knockdown (Figure 7C). RGS5 has been described as negative regulator of Gαq signalling 9,48 .…”

“…This study shows that ageing compromises pericyte coverage in the heart and identifies the Regulator of G-protein signalling isoform 5 (RGS5) as a crucial regulator of pericyte function in the heart. RGS5 belongs to a family of proteins that act as activators of GTPases and has been described to regulate G-protein coupled receptors (GPCR) signalling, acting as inhibitor of Gαq and Gαi 9 . In smooth muscle cells RGS5 has been shown to regulate proliferation 10 and contraction 11 .…”

Label-free Assessment of the Nascent State of Rat Non-alcoholic Fatty Liver Disease Using Spontaneous Raman Microscopy

“…Clear supernatants were collected and the protein concentrations of the samples were determined using a BCA assay (FUJIFILM Wako Pure Chemical Corporation, Osaka, Japan). After dilution of the samples to a final concentration of 0.2 mg/mL with 0.1× sample buffer (ProteinSimple, San Jose, CA, USA), Wes immunoassays were performed using the 12–230 kDa Jess/Wess Separation Module (ProteinSimple) [ 1 , 5 ] according to the manufacturer’s instructions. The primary antibody for adipophilin (1:10, mouse monoclonal antibody, clone: AP125; PROGEN Biotechnik GmbH, Heidelberg, Germany) was used to analyze adipophilin expression.…”