title: Regulator of G protein signaling 2 deficiency causes endothelial dysfunction and impaired endothelium-derived hyperpolarizing factor-mediated relaxation by dysregulating Gi/o signaling.
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.
authors.affiliation: Department of Cell Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Osei-Owusu
authors.forename: Rasna
authors.initials: R
authors.lastname: Sabharwal
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Kaltenbronn
authors.forename: Man-Hee
authors.initials: MH
authors.lastname: Rhee
authors.forename: Mark W
authors.initials: MW
authors.lastname: Chapleau
authors.forename: Hans H
authors.initials: HH
authors.lastname: Dietrich
authors.forename: Kendall J
authors.initials: KJ
authors.lastname: Blumer
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001685:Biological Factors / Q000494:pharmacology / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism*; D065128:Endothelin Receptor Antagonists; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006439:Hemodynamics; D006973:Hypertension / Q000378:metabolism; D066298:In Vitro Techniques; D008638:Mesenteric Arteries / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors; D037342:Pertussis Toxin / Q000494:pharmacology; D020710:RGS Proteins / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001685:Biological Factors; D016861:Cyclooxygenase Inhibitors; D065128:Endothelin Receptor Antagonists; D020710:RGS Proteins; C105345:Rgs2 protein, mouse; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester