Abstract
Regulator of G protein signaling 2 (RGS2) is a GTPase-activating protein for G(q/11)α and G(i/o)α subunits. RGS2 deficiency is linked to hypertension in mice and humans, although causative mechanisms are not understood. Because endothelial dysfunction and increased peripheral resistance are hallmarks of hypertension, determining whether RGS2 regulates microvascular reactivity may reveal mechanisms relevant to cardiovascular disease. Here we have determined the effects of systemic versus endothelium- or vascular smooth muscle-specific deletion of RGS2 on microvascular contraction and relaxation. Contraction and relaxation of mesenteric resistance arteries were analyzed in response to phenylephrine, sodium nitroprusside, or acetylcholine with or without inhibitors of nitric oxide (NO) synthase or K(+) channels that mediate endothelium-derived hyperpolarizing factor (EDHF)-dependent relaxation. The results showed that deleting RGS2 in vascular smooth muscle had minor effects. Systemic or endothelium-specific deletion of RGS2 strikingly inhibited acetylcholine-evoked relaxation. Endothelium-specific deletion of RGS2 had little effect on NO-dependent relaxation but markedly impaired EDHF-dependent relaxation. Acute, inducible deletion of RGS2 in endothelium did not affect blood pressure significantly. Impaired EDHF-mediated vasodilatation was rescued by blocking G(i/o)α activation with pertussis toxin. These findings indicated that systemic or endothelium-specific RGS2 deficiency causes endothelial dysfunction resulting in impaired EDHF-dependent vasodilatation. RGS2 deficiency enables endothelial G(i/o) activity to inhibit EDHF-dependent relaxation, whereas RGS2 sufficiency facilitates EDHF-evoked relaxation by squelching endothelial G(i/o) activity. Mutation or down-regulation of RGS2 in hypertension patients therefore may contribute to endothelial dysfunction and defective EDHF-dependent relaxation. Blunting G(i/o) signaling might improve endothelial function in such patients.
Highlights
Vascular dysfunction and hypertension caused by Regulator of G protein signaling 2 (RGS2) deficiency occur by poorly understood mechanisms
In addition to discovering that endothelial RGS2 deficiency causes endothelial dysfunction characterized by impaired endothelium-derived hyperpolarizing factor (EDHF)-dependent vasodilatation, our studies uncover a new role for endothelial Gi/o signaling and suggest means of ameliorating endothelial dysfunction caused by RGS2 deficiency, which may be relevant to hypertension patients when RGS2 is mutated or down-regulated
Using mesenteric arteries (MA) preconstricted with PE (100 mol/liter), we found that RGS2 deficiency dramatically impaired ACh efficacy (WT ϭ 86% relaxation Ϯ 2 versus RGS2Ϫ/Ϫ ϭ 42% Ϯ 5; p Ͻ 0.001; Fig. 1, C and D) and modestly blunted ACh potency
Summary
Vascular dysfunction and hypertension caused by RGS2 deficiency occur by poorly understood mechanisms. Results: Endothelial RGS2 deficiency impaired endothelium-derived hyperpolarizing factor-mediated relaxation of resistance arteries by a pertussis toxin-sensitive mechanism, without increasing blood pressure significantly. Agonists for G protein-coupled receptors (GPCRs) trigger arterial relaxation by stimulating endothelial production of NO, vasodilatory arachidonic acid metabolites, and endothelium-derived hyperpolarizing factor (EDHF) [1,2,3,4,5] Defects in these mechanisms contribute to aspects of endothelial dysfunction in several diseases, including hypertension, atherosclerosis, diabetes, and preeclampsia [6]. RGS2 potentially regulates blood pressure by several mechanisms because it is expressed in vasculature, kidney, and other tissues and has several biochemical functions [36, 37], including GTPase-activating protein (GAP) activity toward Gq/11 and Gi/o classes of G␣ subunits; GAP-independent inhibition of certain adenylyl cyclase isoforms; phosphorylation and activation by type I␣ cGMP-dependent protein kinase; and association with certain GPCRs and scaffold proteins. In addition to discovering that endothelial RGS2 deficiency causes endothelial dysfunction characterized by impaired EDHF-dependent vasodilatation, our studies uncover a new role for endothelial Gi/o signaling and suggest means of ameliorating endothelial dysfunction caused by RGS2 deficiency, which may be relevant to hypertension patients when RGS2 is mutated or down-regulated
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