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Regulator of G protein signaling 2 deficiency causes endothelial dysfunction and impaired endothelium-derived hyperpolarizing factor-mediated relaxation by dysregulating Gi/o signaling
Journal article   Open access   Peer reviewed

Regulator of G protein signaling 2 deficiency causes endothelial dysfunction and impaired endothelium-derived hyperpolarizing factor-mediated relaxation by dysregulating Gi/o signaling

Patrick Osei-Owusu, Rasna Sabharwal, Kevin M Kaltenbronn, Man-Hee Rhee, Mark W Chapleau, Hans H Dietrich and Kendall J Blumer
The Journal of biological chemistry, Vol.287(15), pp.12541-12549
04/06/2012
DOI: 10.1074/jbc.M111.332130
PMCID: PMC3321003
PMID: 22354966
url
https://doi.org/10.1074/jbc.M111.332130View
Published (Version of record) Open Access

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.
 RGS Proteins - genetics Mesenteric Arteries - pathology Mesenteric Arteries - drug effects Vasodilation RGS Proteins - deficiency Endothelin Receptor Antagonists Pertussis Toxin - pharmacology NG-Nitroarginine Methyl Ester - pharmacology Vasodilator Agents - pharmacology Signal Transduction Acetylcholine - pharmacology Endothelial Cells - metabolism Biological Factors - physiology Mice, Inbred C57BL Endothelium, Vascular - physiopathology Gene Knockout Techniques Cyclooxygenase Inhibitors - pharmacology Hypertension - metabolism Mice, Knockout Nitric Oxide Synthase Type III - antagonists & inhibitors Animals Endothelium, Vascular - pathology Mice Hemodynamics In Vitro Techniques GTP-Binding Protein alpha Subunits, Gi-Go - metabolism Biological Factors - pharmacology

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