Zeidan Asad, Broman Jonas, Hellstrand Per, Swärd Karl
Division of Molecular and Cellular Physiology, Department of Physiological Sciences, Lund University, Biomedical Centre, Lund, Sweden.
Arterioscler Thromb Vasc Biol. 2003 Sep 1;23(9):1528-34. doi: 10.1161/01.ATV.0000090129.75275.C2. Epub 2003 Aug 7.
Stretch-induced growth of the vascular wall plays a role in hypertension and neointima formation. Its signal pathways involve integrins, cytoskeleton, membrane receptors, and ion channels, some of which are organized in cholesterol-rich, membrane domains such as lipid rafts or caveolae. This study tested the role of rafts/caveolae in stretch-induced vascular growth by manipulation of membrane cholesterol contents.
Growth and protein synthesis were induced by mechanical stretch of rat portal veins in vitro. Sucrose gradient centrifugation showed stretch-induced tyrosine phosphorylation primarily in fractions containing caveolin-1. Disruption of membrane caveolae with use of methyl-beta-cyclodextrin (mbetacd) reduced weight gain, protein synthesis, and DNA synthesis to levels in unstretched, control veins. These effects were partially reversed by restoration of cellular cholesterol contents. Inhibited growth was associated with abolished activation of extracellular signal-regulated kinase (ERK) 1/2 in response to stretch and endothelin-1 (ET-1) but not to angiotensin II. Inhibition of ET-1 type A (ETA) receptors by RF139317 or endothelin-converting enzyme by phosphoramidone abolished stretch-induced ERK1/2 activation, which was, however, unaffected by removal of the endothelium.
Stretch-induced growth signaling in vascular smooth muscle depends on cholesterol-rich, membrane microdomains by a mechanism involving ETA receptors that respond to endogenous ET-1 production.
血管壁的拉伸诱导生长在高血压和新生内膜形成中起作用。其信号通路涉及整合素、细胞骨架、膜受体和离子通道，其中一些在富含胆固醇的膜结构域如脂筏或小窝中组织。本研究通过操纵膜胆固醇含量来测试脂筏/小窝在拉伸诱导的血管生长中的作用。
通过体外机械拉伸大鼠门静脉诱导生长和蛋白质合成。蔗糖梯度离心显示拉伸诱导的酪氨酸磷酸化主要在含有小窝蛋白-1的组分中。使用甲基-β-环糊精（mbetacd）破坏膜小窝可将体重增加、蛋白质合成和DNA合成降低至未拉伸的对照静脉水平。细胞胆固醇含量的恢复可部分逆转这些作用。生长受抑制与拉伸和内皮素-1（ET-1）刺激后细胞外信号调节激酶（ERK）1/2的激活被消除有关，但对血管紧张素II刺激无影响。RF139317抑制ET-1 A型（ETA）受体或磷酰胺抑制内皮素转化酶可消除拉伸诱导的ERK1/2激活，然而，去除内皮对此无影响。
血管平滑肌中拉伸诱导的生长信号传导依赖于富含胆固醇的膜微结构域，其机制涉及对内源性ET-1产生作出反应的ETA受体。
