Caveolin-1 Deletion Prevents Hypertensive Vascular Remodeling Induced by Angiotensin II.
Caveolin-1 Deletion Prevents Hypertensive Vascular Remodeling Induced by Angiotensin II.
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DOI：
10.1161/hypertensionaha.116.08278
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发表时间：
2017-01
期刊：
影响因子：
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通讯作者：
Rizzo V
中科院分区：
文献类型：
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作者：
Forrester SJ;Elliott KJ;Kawai T;Obama T;Boyer MJ;Preston KJ;Yan Z;Eguchi S;Rizzo V
血管细胞膜微区（caveolae）对血管紧张素II（AngII）诱导的信号转导和下游功能至关重要。我们已经验证了我们的假设，即小窝蛋白-1（Cav 1），血管小窝的主要结构蛋白，通过调节表皮生长因子受体（EGFR）和血管内皮细胞粘附分子-1（VCAM-1）在血管生成素II的血管重塑中起着关键作用。Cav 1 −/−和对照Cav+/+小鼠输注AngII 2周以诱导血管重塑和高血压。AngII输注后，组织学评估显示Cav 1 +/+小鼠与假手术Cav 1 +/+小鼠相比，主动脉、冠状动脉和肾动脉中膜肥大和血管周围纤维化。与对照Cav 1 +/+小鼠相比，AngII输注的Cav 1 +/+小鼠也表现出心脏肥大的表型，心脏重量与体重比增加。相比之下，输注AngII的Cav 1 −/−小鼠显示血管重塑减弱，但不显示心脏肥大。通过遥测评估，在Cav 1 +/+和Cav 1 −/−小鼠中发现了相似水平的AngII诱导的高血压。在Cav 1 +/+小鼠中，AngII增强了主动脉中酪氨酸磷酸化EGFR染色，而在输注AngII的Cav 1 −/−小鼠中减弱。在输注AngII的Cav 1 +/+小鼠的主动脉中也观察到Cav 1和VCAM-1表达增强，但在Cav 1 −/−主动脉中未观察到。血管细胞的实验进一步为我们的体内发现提供了潜在的机制。这些数据表明，Cav 1，可能是小窝，在血管平滑肌和内皮细胞中起着至关重要的作用，在血管重塑和炎症独立于血压或心脏肥大的调节。
It has been proposed that membrane microdomains, caveolae, in vascular cells are critical for signal transduction and downstream functions induced by angiotensin II (AngII). We have tested our hypothesis that caveolin-1 (Cav1), a major structural protein of vascular caveolae, plays a critical role for development of vascular remodeling by AngII via regulation of epidermal growth factor receptor (EGFR) and vascular endothelial adhesion molecule-1 (VCAM-1). Cav1−/− and control Cav+/+ mice were infused with AngII for 2 weeks to induce vascular remodeling and hypertension. Upon AngII infusion, histological assessments demonstrated medial hypertrophy and perivascular fibrosis of aorta and coronary and renal arteries in Cav1+/+ mice compared with sham-operated Cav1+/+ mice. AngII-infused Cav1+/+ mice also showed a phenotype of cardiac hypertrophy with increased heart weight to body weight ratio compared with control Cav1+/+ mice. In contrast, Cav1−/− mice infused with AngII showed attenuation of vascular remodeling but not cardiac hypertrophy. Similar levels of AngII-induced hypertension were found in both Cav1+/+ and Cav1−/− mice as assessed by telemetry. In Cav1+/+ mice, AngII enhanced tyrosine-phosphorylated EGFR staining in the aorta, which was attenuated in Cav1−/− mice infused with AngII. Enhanced Cav1 and VCAM-1 expression was also observed in aorta from AngII-infused Cav1+/+ mice but not in Cav1−/− aorta. Experiments with vascular cells further provided a potential mechanism for our in vivo findings. These data suggest that Cav1, and presumably caveolae, in vascular smooth muscle and the endothelium plays a critical role in vascular remodeling and inflammation independent from blood pressure or cardiac hypertrophy regulation.