PDGF-dependent regulation of regulator of G protein signaling-5 expression and vascular smooth muscle cell functionality

Gunaje, Jagadambika J.; Bahrami, Arya J.; Schwartz, Stephen M.; Daum, Guenter; Mahoney, William M.

doi:10.1152/ajpcell.00348.2010

Cited by 44 publications

(41 citation statements)

References 85 publications

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“…28 MEK inhibition with specific inhibitors PD98059 (or U0126; Online Figure VII) reduces blood pressure in RGS5-deficient mice to WT levels (WT untreated 83.9±3.8 vs KO PD98059 84.0±4.7 mm Hg). PD98059 also abolishes AngII-induced hypertension in RGS5 KO mice (85.7±4.6 mm Hg; Figure 6B), leading to more dramatic changes in MAP in KO mice than in WT controls (ΔMAP: WT 31.7±2.2 vs KO 76.7±3.4 mm Hg).…”

Section: Rgs5 Regulates Blood Pressure Involving Pkc Mek/erk and Rhmentioning

confidence: 99%

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

Holobotovskyy

Manzur

Tare

et al. 2013

Circulation Research

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Integrative Physiology B lood vessels consist of 2 major cell types, endothelial and mural cells, such as pericytes and vascular smooth muscle cells (VSMC), which surround the endothelium. Regulator of G-protein signaling 5 (RGS5) is expressed in mural cells and has emerged as a crucial modulator of vascular pathology in cancer. For instance, we have demonstrated that RGS5 is highly upregulated in angiogenic tumor pericytes.1 Loss of RGS5 results in pericyte maturation and normalization of tumor vasculature.2,3 Moreover, we showed a crucial role for RGS5 in regulating vascular barrier function in tumors and in brain capillaries during ischemia, and also provided the first genetic evidence that RGS5 is involved in vascular wall remodeling in adults. 2A striking feature of RGS5 expression is its dynamic nature in various physiological and pathological states, which indicates a role in adaptive processes. 1,[4][5][6] This is consistent with RGS5 being a member of the extended family of RGS molecules, which are modulators of G-protein-coupled receptors (GPCRs). G-protein signaling pathways rely on rapid on-off kinetics, and RGS molecules act as GTPaseactivating proteins (GAP) for heterotrimeric G proteins and, as such, regulate duration and intensity of signaling events. They contain a highly conserved carboxyl-terminal RGS domain that confers the catalytic function for active Gα subunits. Members of the R4/B subfamily, which include, among others, RGS 2, 4, and 5, are the smallest RGS Original received September 21, 2012; revision received January 7, 2013; accepted January 9, 2013. In December 2012, the average time from submission to first decision for all original research papers submitted to Circulation Research was 14.5 days.

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Section: Rgs5 Regulates Blood Pressure Involving Pkc Mek/erk and Rhmentioning

confidence: 99%

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

Holobotovskyy

Manzur

Tare

et al. 2013

Circulation Research

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“…Moreover, RGS5 expression was downregulated in SMCs of atherosclerotic plaques, and platelet-derived growth factor-BB as one of the most critical mediators of SMC proliferation was shown to acutely repress RGS5 expression in SMCs. 10,11 RGS5 expression is also tightly controlled on the posttranscriptional level via enhanced degradation through the ubiquitin-dependent N-end rule pathway. The Cys-2 residue at the N-terminus of RGS5 is essential for this degradation, and mutants of RGS5 in which this residue cannot reside at the N-terminus (C2A mutant) are stable and long-lived in vivo because of the lacking degradation.…”

mentioning

confidence: 99%

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

Daniel

Prock

Dutzmann

et al. 2016

ATVB

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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.

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“…Indeed, PDGF-B chain expression upregulation was conirmed in DA tissues after birth, and was inhibited by blocking monocyte adhesion using anti-VLA-4 monoclonal antibody treatment [59]. Moreover, the regulator of G-protein signaling 5 (Rgs5) that was found to be enriched in both ECs and SMCs of DA at full-term gestation compared to adjacent aortic cells [22] was suggested to be negatively regulated by PDGF [65]. PDGF-dependent repression of Rgs5 leads to SMC migration and G protein-coupled receptor-mediated-signaling pathways, such as mitogen-activated protein kinase activation, thus contributing to vessel contraction and remodeling [65].…”

Section: Inlammatory Response In Da Ecs During Anatomic Remodelingmentioning

confidence: 95%

“…Moreover, the regulator of G-protein signaling 5 (Rgs5) that was found to be enriched in both ECs and SMCs of DA at full-term gestation compared to adjacent aortic cells [22] was suggested to be negatively regulated by PDGF [65]. PDGF-dependent repression of Rgs5 leads to SMC migration and G protein-coupled receptor-mediated-signaling pathways, such as mitogen-activated protein kinase activation, thus contributing to vessel contraction and remodeling [65]. The Rgs5 expression level in DA tissue after birth has not been studied, but it is reasonable to hypothesize that it would be decreased, likely due to increased PDGF secretion after birth.…”

Section: Inlammatory Response In Da Ecs During Anatomic Remodelingmentioning

confidence: 99%

Unique Phenotypes of Endothelial Cells in Developing Arteries: A Lesson from the Ductus Arteriosus

Liu¹,

Minamisawa²

2017

Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

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Endothelial cells (ECs) play a critical role in regulating vascular pathophysiology. Various growth factors and relaxation factors such as vascular endothelial growth factor (VEGF) and nitric oxide (NO), which are derived from ECs, are known to maintain homeostasis and regulate vessel remodeling. Although the inner lumens of all types of vessels are covered by an EC monolayer, the characteristics of ECs difer in each tissue and developing stage of a vessel. Previously, we identiied the heterogeneity of ECs of the ductus arteriosus (DA) by analyzing its gene proiles. The DA is a fetal artery that closes immediately after birth due to the changes in concentrations of oxygen and vasoactive factors such as NO and prostaglandin E. Studying the unique gene proile of ECs in the DA can therefore uncover the novel key genes involved in developing vascular function and morphology such as O 2 sensitivity and physiological vascular remodeling. A comprehensive gene analysis identiied a number of genes related to morphogenesis and development in the DA. In this chapter, we discuss the heterogeneity of vascular ECs in the developing vessel in the DA.

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PDGF-dependent regulation of regulator of G protein signaling-5 expression and vascular smooth muscle cell functionality

Cited by 44 publications

References 85 publications

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

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

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

Unique Phenotypes of Endothelial Cells in Developing Arteries: A Lesson from the Ductus Arteriosus

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