Placental growth factor mediates aldosterone-dependent vascular injury in mice
Placental growth factor mediates aldosterone-dependent vascular injury in mice
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DOI：
10.1172/jci40205
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发表时间：
2010-11-01
影响因子：
15.9
通讯作者：
Mendelsohn, Michael E.
中科院分区：
文献类型：
--
作者：
Jaffe, Iris Z.;Newfell, Brenna G.;Mendelsohn, Michael E.
在临床试验中，醛固酮拮抗剂通过未知的机制降低心血管缺血和死亡率。醛固酮是一种类固醇激素，通过肾矿化皮质激素受体（MRs）调节血压。MRs在人血管细胞中表达并调控基因转录，提示醛固酮可能对血管有直接作用。通过基因表达谱，我们在小鼠和人类中发现促增殖VEGF家族成员胎盘生长因子（PGF）是醛固酮调节的血管MR靶基因。醛固酮激活的血管MR刺激Pgf基因转录，增加Pgf蛋白在小鼠血管中的表达和分泌。在内皮损伤的小鼠血管和动脉粥样硬化患者的人血管中，醛固酮可增强PGF及其受体fms样酪氨酸激酶1 （Flt1）的表达。在动脉粥样硬化的人血管中，MR拮抗剂抑制PGF的表达。在体内，醛固酮输注增强了小鼠颈动脉损伤后的血管重塑，而在Pgf（/-）小鼠中没有这种作用。综上所述，我们认为PGF是血管MR的一个新的下游靶点，它介导醛固酮增强血管损伤。这些发现提示了醛固酮拮抗剂在人类血管保护作用中的非肾机制，并支持靶向血管醛固酮/MR/PGF/Flt1通路作为缺血性心血管疾病的治疗策略。
In clinical trials, aldosterone antagonists reduce cardiovascular ischemia and mortality by unknown mechanisms. Aldosterone is a steroid hormone that signals through renal mineralocorticoid receptors (MRs) to regulate blood pressure. MRs are expressed and regulate gene transcription in human vascular cells, suggesting that aldosterone might have direct vascular effects. Using gene expression profiling, we identify the pro-proliferative VEGF family member placental growth factor (PGF) as an aldosterone-regulated vascular MR target gene in mice and humans. Aldosterone-activated vascular MR stimulated Pgf gene transcription and increased PGF protein expression and secretion in the mouse vasculature. In mouse vessels with endothelial damage and human vessels from patients with atherosclerosis, aldosterone enhanced expression of PGF and its receptor, FMS-like tyrosine kinase 1 (Flt1). In atherosclerotic human vessels, MR antagonists inhibited PGF expression. In vivo, aldosterone infusion augmented vascular remodeling in mouse carotids following wire injury, an effect that was lost in Pgf(/-) mice. In summary, we have identified PGF as what we believe to be a novel downstream target of vascular MR that mediates aldosterone augmentation of vascular injury. These findings suggest a non-renal mechanism for the vascular protective effects of aldosterone antagonists in humans and support targeting the vascular aldosterone/MR/PGF/Flt1 pathway as a therapeutic strategy for ischemic cardiovascular disease.