Small G Proteins in the Cardiovascular System: Physiological and Pathological Aspects

Abstract

Small G proteins exist in eukaryotes from yeast to human and constitute the Ras superfamily comprising more than 100 members. This superfamily is structurally classified into five families: the Ras, Rho, Rab, Arf, and Ran families that control a wide variety of cell and biological functions through highly coordinated regulation processes. Increasing evidence has accumulated to identify small G proteins and their regulators as key players of the cardiovascular physiology that control a large panel of cardiac (heart rhythm, contraction, hypertrophy) and vascular functions (angiogenesis, vascular permeability, vasoconstriction). Indeed, basal Ras protein activity is required for homeostatic functions in physiological conditions, but sustained overactivation of Ras proteins or spatiotemporal dysregulation of Ras signaling pathways has pathological consequences in the cardiovascular system. The primary object of this review is to provide a comprehensive overview of the current progress in our understanding of the role of small G proteins and their regulators in cardiovascular physiology and pathologies.

Genetic Dissection of the Vav2-Rac1 Signaling Axis in Vascular Smooth Muscle Cells

“…We demonstrated before that Rhog Ϫ/Ϫ mice do not develop hypertension (17), ruling out the implication of RhoG in Vav2-dependent roles in vascular tone regulation. It also is unlikely that such function is mediated by RhoA, given the wellknown implication of this GTPase in vasoconstriction-related vSMC responses (1). To investigate the implication of the remaining GTPases in this signaling route, we generated new mouse strains that allowed the specific, chemically inducible depletion of either Rac1 or Cdc42 in SMCs.…”

“…T he dynamic regulation of the contractile behavior of vSMCs is one of the main mechanisms used by organisms to maintain blood pressure levels under both physiological and hypertensive conditions (1). Vasoconstriction is mediated primarily by pressor molecules, such as angiotensin II (AngII), catecholamines, endothelins, and eicosanoids.…”

“…4A). In addition to blood pressure control, vSMCs participate in a variety of vascularrelated processes, including the development of hypertension-dependent and independent pathological states, such as cardiovascular remodeling and neointima formation (1).…”

“…With the notable exception of RhoA, the role of other Rho subfamily GTPases in vSMCs remains poorly characterized (1). The function of Rac1 is particularly unsettled, since available data support its implication in both vasoconstriction (8)(9)(10) and vasodilation (11,12).…”

Leukocyte RhoA exchange factor Arhgef1 mediates vascular inflammation and atherosclerosis

“…Although the role of RhoA in vascular inflammation and atherosclerosis has not been directly addressed, evidence, mainly supported by the beneficial effect of Rho kinase inhibitors, suggested that RhoA/ Rho kinase signaling in vascular and hematopoietic cells participates in multiple steps of atherogenesis, including endothelial cell activation and dysfunction; leukocyte recruitment and cytokine and chemokine release; and oxidized LDL uptake in macrophage and foam cell formation (29). By showing a restricted role of Arhgef1 in leukocytes and in their recruitment to the endothelium, our data support the concept that RhoA GEFs discriminate upstream signals and that, depending on the cell type and the upstream activator, the RhoA GEF responsible for RhoA activation is different.…”