Kalmes A, Daum G, Clowes A W
Department of Surgery, University of Washington, Seattle 98195-6410, USA.
Ann N Y Acad Sci. 2001 Dec;947:42-54; discussion 54-5. doi: 10.1111/j.1749-6632.2001.tb03929.x.
Vascular smooth muscle cells (SMCs) are the principal cellular component of the normal artery and intimal lesions that develop in response to arterial injury. Several growth factors and their receptors participate in SMC activation, including the tyrosine kinase receptors for platelet-derived growth factor (PDGF) and basic fibroblast growth factor as well as the G-protein-coupled receptors (GPCRs) for thrombin and angiotensin II. During the last couple of years, it has become evident that GPCRs transactivate receptor tyrosine kinases, particularly the epidermal growth factor receptor (EGFR). The EGFR is not well characterized in terms of its role in vascular biology, but recent findings indicate that GPCRs induce EGFR transactivation in cultured vascular SMCs, perhaps by intracellular and extracellular pathways. Studies from our laboratory as well as two other groups have demonstrated that EGFR transactivation by different GPCR agonists and in different cell types, including SMCs, is mediated by heparin-binding EGF-like growth factor (HB-EGF). HB-EGF-dependent EGFR activation is blocked by heparin, a growth inhibitor of SMCs in vitro and in vivo. These data suggest that the EGFR may be important in the regulation of SMC function. The complexity of the GPCR-EGFR crosstalk, involving several different cell surface molecules and an inside-out signaling step, may provide novel targets for the control of SMC growth and intimal hyperplasia in the arterial injury response.
血管平滑肌细胞（SMCs）是正常动脉以及因动脉损伤而形成的内膜病变的主要细胞成分。几种生长因子及其受体参与平滑肌细胞的激活，包括血小板衍生生长因子（PDGF）和碱性成纤维细胞生长因子的酪氨酸激酶受体，以及凝血酶和血管紧张素II的G蛋白偶联受体（GPCRs）。在过去几年中，越来越明显的是，GPCRs可转激活受体酪氨酸激酶，特别是表皮生长因子受体（EGFR）。EGFR在血管生物学中的作用尚未得到充分表征，但最近的研究结果表明，GPCRs可能通过细胞内和细胞外途径在培养的血管平滑肌细胞中诱导EGFR转激活。我们实验室以及其他两个研究小组的研究表明，不同的GPCR激动剂在不同细胞类型（包括平滑肌细胞）中诱导的EGFR转激活是由肝素结合表皮生长因子样生长因子（HB-EGF）介导的。HB-EGF依赖性EGFR激活可被肝素阻断，肝素是平滑肌细胞在体外和体内的生长抑制剂。这些数据表明，EGFR可能在平滑肌细胞功能的调节中起重要作用。GPCR-EGFR相互作用的复杂性，涉及几种不同的细胞表面分子和一个由内而外的信号传导步骤，可能为控制动脉损伤反应中的平滑肌细胞生长和内膜增生提供新的靶点。
