Review article
Regulator of G Protein Signaling 5: A New Player in Vascular Remodeling

https://doi.org/10.1016/j.tcm.2009.04.002Get rights and content

Regulators of G protein signaling (RGS) proteins are important modulators of G protein-coupled receptors and, therefore, critical for cardiovascular functions. One family member, RGS5, has recently been identified as a key regulator of vascular remodeling and pericyte maturation in tumors. Here, we discuss a potential role for RGS5 and its relatives, RGS2 and 4, within the cardiovascular system. Insights into RGS5 signaling are likely to be highly significant for vascular pathologies such as hypertension, atherosclerosis, and angiogenesis.

Section snippets

A Critical Role of Regulators of G Protein Signaling Proteins in G Protein-Coupled Receptor Signaling

G protein-coupled receptors (GPCRs) are essential regulators of biologic processes. In the cardiovascular system alone, several hundred GPCRs are expressed and regulate key functions such as vascular tone and heart rate (Tang and Insel 2004). Coupled to GPCRs are heterotrimeric G proteins that act as signal transducers and are classified into four categories based on the functional and structural similarities of the α subunit; the Gαs subfamily stimulates adenylyl cyclase (AC) activity; Gαi/o

An Emerging Role of RGS Molecules in Cardiovascular Function

Recently, there has been an exponential increase in studies on RGS molecules and their signaling activities. However, these data are mainly derived from reconstituted in vitro systems, where RGS molecules are overexpressed along with GPCRs and very little is known of their physiologic relevance in vivo. In view of this, RGS knockout and transgenic mouse models are now being developed and provide us with new insights into complex systems, including their role in cardiovascular function (Table 1

A Newly Discovered Role of RGS5 in Vascular Remodeling

RGS5, another member of the B/R4 family, is expressed in most major organs, including the heart, lungs, skeletal muscle, brain, kidneys, and placenta, as well as in highly specialized cell types such as vascular smooth muscle cells, glomerular mesangial cells of the kidney, and cardiac myocytes (Seki et al. 1998). Interestingly, gene expression studies revealed that RGS5 expression is dynamically regulated in vivo, which is in line with RGS5 being a regulator of adaptive processes and vascular

RGS5 as a Regulator of Cardiovascular Function

Pericytes have been associated with hemodynamic functions, similar to SMC of larger vessels, and can control vasoconstriction and vasodilation within capillary beds (Bergers and Song 2005). Thus, although it is possible that pericytes also play a role in blood pressure homeostasis, they represent a heterogeneous cell population, and a conclusive link to RGS5 is yet to be made. Interestingly, however, RGS5 is expressed early during arterial development (Bondjers et al., 2003, Cho et al., 2003)

Regulatory Networks of RGS2 and 5 in vSMC

RGS5 knockout mice have only recently been generated, and therefore, most signaling studies have been conducted in cell culture. In contrast, the role of RGS2 in cardiovascular function has been analyzed in an elegant combination of in vivo and in vitro studies using gene knockout mice (Table 1). RGS2 preferentially interacts with Gαq (Heximer et al. 1999) and attenuates signaling via Gαq-coupled GPCR receptors such as PAR1/thrombin, α-adrenergic receptor/phenylephrine, and angiotensin II

Concluding Remarks

Cardiovascular diseases, including hypertension, heart failure, and atherosclerosis, remain one of the largest causes of morbidity and mortality in Western populations. GPCR-mediated signaling is critical for normal function in the cardiovascular system and is currently the primary target for the pharmacologic treatment of disease. There is a growing interest in RGS molecules because their role as specific GPCR modulators emerges. In particular, RGS2 and RGS4 have been recognized as important

Acknowledgments

The authors acknowledge support for their original work summarized in this article from the National Health and Medical Research Council, Australia, the Western Australian Institute for Medical Research, and the University of Western Australia, Perth, Western, Australia.

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