Rgs5 Targeting Leads to Chronic Low Blood Pressure and a Lean Body Habitus

Abstract

RGS5 is a potent GTPase-activating protein for G i␣ and G q␣ that is expressed strongly in pericytes and is present in vascular smooth muscle cells. To study the role of RGS5 in blood vessel physiology, we generated Rgs5-deficient mice. The Rgs5 ؊/؊ mice developed normally, without obvious defects in cardiovascular development or function. Surprisingly, Rgs5 ؊/؊ mice had persistently low blood pressure, lower in female mice than in male mice, without concomitant cardiac dysfunction, and a lean body habitus. The examination of the major blood vessels revealed that the aortas of Rgs5 ؊/؊ mice were dilated compared to those of control mice, without altered wall thickness. Isolated aortic smooth muscle cells from the Rgs5 ؊/؊ mice exhibited exaggerated levels of phosphorylation of vasodilator-stimulated phosphoprotein and extracellular signal-regulated kinase in response to stimulation with either sodium nitroprusside or sphingosine 1-phosphate. The results of this study, along with those of previous studies demonstrating that RGS5 stability is under the control of nitric oxide via the N-end rule pathway, suggest that RGS5 may balance vascular tone by attenuating vasodilatory signaling in vivo in opposition to RGS2, another RGS (regulator of G protein signaling) family member known to inhibit G protein-coupled receptor-mediated vasoconstrictor signaling. Blocking the function or the expression of RGS5 may provide an alternative approach to treat hypertension.The maintenance of normal blood pressure (BP) is achieved in part by balancing the constriction and dilatation of resistance arterioles via vasoregulatory G protein-coupled receptors (GPCRs). When activated by ligand binding, these GPCRs function as guanine nucleotide exchange factors for heterotrimeric G proteins, triggering downstream effectors and thus producing the biological responses attributed to these receptors. The GTPase activity of G ␣ subunits is subject to control by GTPase-activating proteins (GAPs) called regulators of G protein signaling (RGS) proteins. RGS proteins limit the duration that G ␣ subunits remain GTP bound, thereby negatively regulating GPCR-mediated signaling pathways. Numerous studies with genetically modified animals and with genetic polymorphisms of human populations have underscored the importance of GPCR agonists, GPCRs, and components of GPCR-mediated signaling pathways in BP homeostasis (for a review, see reference 24).A member of the RGS family, RGS2, and GPCR kinase 2 (GRK2), GRK4, and GRK5 have been implicated previously in the regulation of BP. RGS2 is a potent negative regulator of G q␣ , and mice lacking RGS2 are hypertensive due to prolonged signaling by vasoconstrictor GPCR signaling pathways involved in BP control (12). The overexpression of GRK2 or GRK5 in vascular smooth muscle cells (VSMC) also results in a hypertensive phenotype by decreasing GPCR-mediated vasodilation and simultaneously enhancing GPCR-mediated vasoconstriction (8,15). A defective coupling between the dopamine receptor and the G protein-effector ...

Regulator of G-Protein Signaling 5 Controls Blood Pressure Homeostasis and Vessel Wall Remodeling

“…[18][19][20] In earlier studies, RGS5-deficient mice have been shown to be hypotensive relative to wild-type (WT) controls. 21,22 This remains an unexpected finding and difficult to reconcile with our current understanding of the function of RGS5 as a negative regulator of vasoconstriction. 8,9 Here, we demonstrate that loss of RGS5 results in hypertension, a finding that is supported by complementary functional assays.…”

Genetic, epigenetic, and gene-by-diet interaction effects underlie variation in serum lipids in a LG/J×SM/J murine model

“…This same QTL region has been mapped in approximately 15 different crosses of mouse strains ( 28 ), and the candidate genes in the region are well studied in mouse models of CVD risk (44)(45)(46)(47)(48). The gene Hsd17b7 located in this region has been shown to play a role in cholesterol biosynthesis in both mice and humans ( 46 ).…”

ABCG2pos lung mesenchymal stem cells are a novel pericyte subpopulation that contributes to fibrotic remodeling

“…It is considered a marker of rare pericytes (10), and its expression is typically not detected in adult lung (72). Its expression has been associated with vascular remodeling, rarefaction, or loss of microvessels and regulation of vascular tone (21,35,36,74). Periostin is a profibrotic and proinflammatory protein hypothesized to be a potential biomarker in IPF (68,93).…”