醛固酮通过直接作用于血管平滑肌细胞的盐皮质激素受体促进血管重构。
Aldosterone promotes vascular remodeling by direct effects on smooth muscle cell mineralocorticoid receptors.
机构信息
From the Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (D.P., A.M., M.A., C.G., I.Z.J.); and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA (S.A.K.).
出版信息
Arterioscler Thromb Vasc Biol. 2014 Feb;34(2):355-64. doi: 10.1161/ATVBAHA.113.302854. Epub 2013 Dec 5.
OBJECTIVE
Vascular remodeling occurs after endothelial injury, resulting in smooth muscle cell (SMC) proliferation and vascular fibrosis. We previously demonstrated that the blood pressure-regulating hormone aldosterone enhances vascular remodeling in mice at sites of endothelial injury in a placental growth factor-dependent manner. We now test the hypothesis that SMC mineralocorticoid receptors (MRs) directly mediate the remodeling effects of aldosterone and further explore the mechanism.
APPROACH AND RESULTS
A wire-induced carotid injury model was performed in wild-type mice and mice with inducible SMC-specific deletion of the MR. Aldosterone did not affect re-endothelialization after injury in wild-type mice. Deletion of SMC-MR prevented the 79% increase in SMC proliferation induced by aldosterone after injury in MR-Intact littermates. Moreover, both injury-induced and aldosterone-enhanced vascular fibrosis were attenuated in SMC-specific MR knockout mice. Further exploration of the mechanism revealed that aldosterone-induced vascular remodeling is prevented by in vivo blockade of the placental growth factor-specific receptor, type 1 vascular endothelial growth factor receptor (VEGFR1), the receptor for placental growth factor. Immunohistochemistry of carotid vessels shows that the induction of VEGFR1 expression in SMC after vascular injury is attenuated by 72% in SMC-specific MR knockout mice. Moreover, aldosterone induction of vascular placental growth factor mRNA expression and protein release are also prevented in vessels lacking SMC-MR.
CONCLUSIONS
These studies reveal that SMC-MR is necessary for aldosterone-induced vascular remodeling independent of renal effects on blood pressure. SMC-MR contributes to induction of SMC VEGFR1 in the area of vascular injury and to aldosterone-enhanced vascular placental growth factor expression and hence the detrimental effects of aldosterone are prevented by VEGFR1 blockade. This study supports exploring MR antagonists and VEGFR1 blockade to prevent pathological vascular remodeling induced by aldosterone.
目的
血管重构发生于血管内皮损伤后，导致平滑肌细胞（SMC）增殖和血管纤维化。我们之前的研究表明，调节血压的激素醛固酮以胎盘生长因子（PlGF）依赖的方式增强内皮损伤部位的小鼠血管重构。我们现在检验假设，即 SMC 盐皮质激素受体（MR）直接介导醛固酮的重构作用，并进一步探讨其机制。
方法和结果
在野生型小鼠和SMC 特异性诱导 MR 缺失的小鼠中进行了导丝诱导的颈动脉损伤模型。醛固酮对野生型小鼠损伤后的再内皮化没有影响。SMC-MR 的缺失阻止了损伤后 MR 完整同窝仔鼠中醛固酮诱导的 SMC 增殖增加 79%。此外，SMC 特异性 MR 敲除小鼠的损伤诱导和醛固酮增强的血管纤维化均减弱。进一步的机制研究表明，血管 PlGF 特异性受体 1 型血管内皮生长因子受体（VEGFR1），即 PlGF 的受体，体内阻断可预防醛固酮诱导的血管重构。颈动脉血管的免疫组织化学显示，SMC 特异性 MR 敲除小鼠中血管损伤后 SMC 中 VEGFR1 表达的诱导降低了 72%。此外，缺乏 SMC-MR 的血管中醛固酮诱导的血管 PlGF mRNA 表达和蛋白释放也被阻止。
结论
这些研究表明，SMC-MR 是醛固酮诱导的血管重构所必需的，与肾对血压的影响无关。SMC-MR 有助于在血管损伤区域诱导 SMC VEGFR1，并增强醛固酮增强的血管 PlGF 表达，因此 VEGFR1 阻断可预防醛固酮的有害作用。本研究支持探索 MR 拮抗剂和 VEGFR1 阻断以预防醛固酮诱导的病理性血管重构。
Zotero 插件