Department of Cell Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Biol Chem. 2012 Apr 6;287(15):12541-9. doi: 10.1074/jbc.M111.332130. Epub 2012 Feb 21.
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.
G 蛋白信号调节因子 2（RGS2）是 Gq/11α 和 Gi/oα 亚基的 GTP 酶激活蛋白。RGS2 缺乏与小鼠和人类的高血压有关，但因果机制尚不清楚。由于内皮功能障碍和外周阻力增加是高血压的标志，因此确定 RGS2 是否调节微血管反应性可能揭示与心血管疾病相关的机制。在这里，我们已经确定了系统性或内皮细胞或血管平滑肌特异性 RGS2 缺失对微血管收缩和舒张的影响。在存在或不存在一氧化氮（NO）合酶或介导内皮衍生超极化因子（EDHF）依赖性舒张的 K+通道抑制剂的情况下，分析了对 phenylephrine、sodium nitroprusside 或 acetylcholine 的肠系膜阻力血管收缩和舒张。结果表明，血管平滑肌中 RGS2 的缺失影响较小。系统性或内皮细胞特异性 RGS2 缺失显着抑制乙酰胆碱引起的舒张。内皮细胞特异性 RGS2 缺失对 NO 依赖性舒张几乎没有影响，但显着损害 EDHF 依赖性舒张。内皮细胞中 RGS2 的急性、诱导性缺失对血压没有显着影响。用百日咳毒素阻断 G(i/o)α 激活可挽救受损的 EDHF 介导的血管舒张。这些发现表明，系统性或内皮细胞特异性 RGS2 缺乏导致内皮功能障碍，导致 EDHF 依赖性血管舒张受损。RGS2 缺乏使内皮细胞 G(i/o) 活性能够抑制 EDHF 依赖性舒张，而 RGS2 充足通过抑制内皮细胞 G(i/o) 活性促进 EDHF 引起的舒张。因此，高血压患者中 RGS2 的突变或下调可能导致内皮功能障碍和 EDHF 依赖性舒张缺陷。抑制 G(i/o)信号可能会改善此类患者的内皮功能。
