G12-G13-LARG-mediated signaling in vascular smooth muscle is required for salt-induced hypertension
G12-G13-LARG-mediated signaling in vascular smooth muscle is required for salt-induced hypertension
复制标题
DOI：
10.1038/nm1666
复制
发表时间：
2008-01-01
期刊：
影响因子：
82.9
通讯作者：
Offermanns, Stefan
中科院分区：
文献类型：
--
作者：
Wirth, Angela;Benyo, Zoltan;Offermanns, Stefan
血管平滑肌细胞的张力是总外周血管阻力以及动脉血压的主要决定因素。大多数形式的高血压最终都是由于血管张力增加导致总外周阻力升高(1-3)。正常血压和高血压条件下血管阻力的调节涉及多种介质，其中许多介质通过血管平滑肌细胞上的 G 蛋白偶联受体发挥作用 (4)。介导血管收缩的受体与 G 蛋白 G(q)-G(11) 和 G(12)-G(13) 偶联，分别通过 Ca2+/MLC 激酶和 Rho/Rho 激酶介导的信号通路刺激肌球蛋白轻链 (MLC) 磷酸化 (4-6)。使用基因改变的小鼠模型，通过平滑肌细胞中可诱导的 Cre/loxP 介导的诱变来急性废除两条信号传导途径，我们表明平滑肌细胞中的 G(q)-G(11) 介导的信号传导是维持基础血压和盐诱导高血压的发展所必需的。相比之下，G(12)-G(13)及其主要效应子——白血病相关的Rho鸟嘌呤核苷酸交换因子(LARG)的缺乏不会改变正常的血压调节，但确实阻止了盐诱发的高血压的发展。这将 G(12)-G(13)-LARG 介导的信号通路确定为抗高血压治疗的新靶标，预计不会影响正常的血压调节。
The tone of vascular smooth muscle cells is a primary determinant of the total peripheral vascular resistance and hence the arterial blood pressure. Most forms of hypertension ultimately result from an increased vascular tone that leads to an elevated total peripheral resistance(1-3). Regulation of vascular resistance under normotensive and hypertensive conditions involves multiple mediators, many of which act through G protein-coupled receptors on vascular smooth muscle cells(4). Receptors that mediate vasoconstriction couple with the G-proteins G(q)-G(11) and G(12)-G(13) to stimulate phosphorylation of myosin light chain (MLC) via the Ca2+/MLC kinase- and Rho/Rho kinase-mediated signaling pathways, respectively(4-6). Using genetically altered mouse models that allow for the acute abrogation of both signaling pathways by inducible Cre/loxP-mediated mutagenesis in smooth muscle cells, we show that G(q)-G(11)-mediated signaling in smooth muscle cells is required for maintenance of basal blood pressure and for the development of salt-induced hypertension. In contrast, lack of G(12)-G(13), as well as of their major effector, the leukemiaassociated Rho guanine nucleotide exchange factor (LARG), did not alter normal blood pressure regulation but did block the development of salt-induced hypertension. This identifies the G(12)-G(13)-LARG-mediated signaling pathway as a new target for antihypertensive therapies that would be expected to leave normal blood pressure regulation unaffected.