Rap1b in smooth muscle and endothelium is required for maintenance of vascular tone and normal blood pressure.
Rap1b in smooth muscle and endothelium is required for maintenance of vascular tone and normal blood pressure.
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DOI：
10.1161/atvbaha.114.303678
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发表时间：
2014-07
期刊：
影响因子：
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通讯作者：
Chrzanowska-Wodnicka M
中科院分区：
文献类型：
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作者：
Lakshmikanthan S;Zieba BJ;Ge ZD;Momotani K;Zheng X;Lund H;Artamonov MV;Maas JE;Szabo A;Zhang DX;Auchampach JA;Mattson DL;Somlyo AV;Chrzanowska-Wodnicka M
小GTdR ap 1b控制着几种基本的细胞现象，其在小鼠中的缺失导致几种心血管缺陷，包括血细胞粘附受损和血管生成缺陷。我们发现Rap 1b敲除（Rap 1b −/−）小鼠会发生心脏肥大和高血压。因此，我们研究了Rap 1b在血压调节中的功能。Rap 1b −/−小鼠出现心脏肥大和血压升高，但保持正常心率。用氯沙坦纠正血压升高，血管紧张素II I型受体减轻了Rap 1b −/−小鼠的心脏肥大，表明心脏肥大可能继发于高血压。Rap 1b −/−小鼠的肾功能和血浆肾素活性指数正常。在体外，我们研究了Rap 1b缺失对平滑肌（SM）介导的血管收缩和内皮依赖性血管扩张（控制基础血管张力的两种主要机制）的影响是否是高血压的基础。我们发现，在基础条件下，用血栓素类似物或血管紧张素II或苯丙氨酸沿着肌球蛋白磷酸酶抑制性磷酸化的增加，与基础张力升高和观察到的高血压一致。Rap 1b −/−小鼠的血管对Rap 1激活剂Epac的cAMP依赖性舒张反应降低。血管内皮细胞对血流量增加的反应性舒张性一氧化氮（NO）释放不足导致高血压。我们发现，NO依赖性血管舒张在Rap 1b缺陷的血管显着抑制。这是第一份报告表明，Rap 1b在SM和内皮细胞中通过控制正常的血管张力在维持血压中起着关键作用。
Small GTPase Rap1b controls several basic cellular phenomena and its deletion in mice leads to several cardiovascular defects, including impaired adhesion of blood cells and defective angiogenesis. We found that Rap1b knockout (Rap1b−/−) mice develop cardiac hypertrophy and hypertension. Therefore, we examined the function of Rap1b in regulation of blood pressure. Rap1b−/− mice developed cardiac hypertrophy and elevated blood pressure, but maintained a normal heart rate. Correcting elevated blood pressure with losartan, an angiotensin II type I receptor alleviated cardiac hypertrophy in Rap1b−/− mice, suggesting a possibility that cardiac hypertrophy develops secondary to hypertension. The indices of renal function and plasma renin activity were normal in Rap1b−/− mice. Ex vivo, we examined whether the effect of Rap1b-deletion on smooth muscle (SM)-mediated vessel contraction and endothelium-dependent vessel dilation, two major mechanisms controlling basal vascular tone, were the basis for the hypertension. We found increased contractility upon stimulation with a thromboxane analogue or Angiotensin II or phenylephrine along with increased inhibitory phosphorylation of myosin phosphatase under basal conditions consistent with elevated basal tone and the observed hypertension. cAMP-dependent-relaxation in response to Rap1 activator, Epac, was decreased in vessels from Rap1b−/− mice. Defective endothelial release of dilatory nitric oxide (NO) in response to elevated blood flow leads to hypertension. We found that NO-dependent vasodilation was significantly inhibited in Rap1b-deficient vessels. This is the first report to indicate that Rap1b in both SM and endothelium plays a key role in maintaining blood pressure by controlling normal vascular tone.