EGF RECEPTOR IN SMOOTH MUSCLE CELL FUNCTION

肝素及其相关的硫酸肝素糖胺聚糖可抑制平滑肌细胞(SMC)的增殖和迁移。这一观察具有重要意义，因为硫酸乙酰肝素蛋白多糖可能在调节正常动脉壁中SMC的生长状态方面发挥作用。肝素抑制凝血酶和血清激活的SMC，但不抑制PDGF-BB。在初步实验中，我们已经证明凝血酶信号部分是通过肝素结合的EGF样生长因子(HB-EGF)、EGF受体(EGFR)的激活而介导的，并且不被肝素阻断。本研究的主要目的是验证三个假说：1.体外和体内的SMC迁移需要EGFR的激活；2.PDGF-BB和凝血酶利用不同的机制反式激活EGFR；3.EGFR的激活诱导硫酸乙酰肝素蛋白多糖的表达，进而调节EGFR的功能。我们提出了一种体外和体内相结合的方法，利用培养的恒河猴和大鼠的SMCs，球囊损伤的大鼠颈动脉，以及调节HB-EGF，EGFR，PDGFR和凝血酶受体功能的药物策略。

Heparin and related heparan sulfate glycosaminoglycans inhibit smooth muscle cell (SMC) proliferation and migration. This observation is of significance because heparan sulfate proteoglycans may play a role in regulating the growth state of SMCs in the normal arterial wall. Heparin inhibits SMC activation by thrombin and serum but not PDGF-BB. In preliminary experiments, we have shown that thrombin signaling is mediated in part by heparin-binding EGF-like growth factor (HB-EGF), activation of the EGF receptor (EGFR), and is not blocked by heparin. The primary objective of this research program is to test three hypotheses: 1. EGFR activation is required for SMC migration in vitro and in vivo; 2. PDGF-BB and thrombin utilize different mechanisms for EGFR transactivation; 3. EGFR activation induces the expression of heparan sulfate proteoglycans that then modulate EGFR function. We propose a combined in vitro and in vivo approach using cultured baboon and rat SMCs, the balloon-injured rat carotid artery, and pharmacological strategies for modulating HB-EGF, EGFR, PDGFR, and thrombin receptor function.