The role of PDGF-B chain after vascular injury

血管成形术后，由于血管平滑肌细胞(SMC)的迁移和增殖而形成新生内膜，许多患者会发生血管狭窄。许多生长因子参与了新生内膜的形成，包括血小板衍生生长因子(PDGF)和血管紧张素II。在这项研究中，我们获得了几个新的发现。首先，我们证明了PDGF在动脉损伤后新生内膜发育过程中的重要作用。我们在大鼠颈动脉球囊损伤模型的新生内膜形成过程中使用了曲普地尔，它被认为是唯一一种几乎选择性地阻断PDGF作用的药物。其次，我们证明了在大鼠模型中，内源性PDGF-B链在同一时期的PDGFs中起着最重要的作用。我们将可溶性PDGF-β受体胞外区(PDGFXR)作为PDGF-B的选择性拮抗剂。在培养的SMC中，我们发现PDGFXR取消了PDGF-B的功能，即刺激PDGF-β受体酪氨酸磷酸化和DNA合成。在大鼠颈动脉球囊损伤模型中，我们发现在新生内膜发育阶段，血小板衍生生长因子-β受体被更显著地激活。将携带PDGFXR基因的腺病毒载体导入损伤的大鼠颈动脉，几乎完全抑制了PDGFR-α受体的激活，减少了新生内膜的形成。第三，我们发现新生内膜SMC在血管紧张素II(Ang II)刺激下产生PDGF-B链。第四，我们证明了Ang II激活了几个分子，这些分子起着信号转导的开关作用。通过RAS、ERK、JNK和Egr-1产生PDGF-B。这些结果表明，PDGF-B链在动脉损伤后新生内膜形成过程中起重要作用。他们还提示，PDGFXR作为一种治疗基因可用于预防动脉损伤后的血管狭窄。

Vascular stenosis occurs in many patients after angioplasty because of neointima formation due to migration and proliferation of vascular smooth muscle cells (SMC). A variety of growth factors have been implicated in neointima formation including platelet-derived growth factor (PDGF) and angiotensin II. In this study, we obtained several new findings. First, we demonstrated the important role of PDGF in the phase of neointimal development after arterial injury. We administered Trapidil, which is thought to be the only drug blocking the action of PDGF almost selectively, during the phase of developing the neointima formation in a rat carotid balloon injured model. Second, we demonstrated endogenous PDGF-B chain among PDGFs played the most imporlant role during the same phase in a rat model. We made the soluble extracellular region of PDGF-β receptor (PDGFXR) as a selective antagonist ofPDGF-B. In cultured SMC, we found PDGFXR abolishes function of PDGF-B i.e. stimulation of PDGF-β receptor tyrosine phosphoroyation and DNA synthesis. In a rat carotid balloon injured model, we demonstrated that PDGF-β receptor is activated more significantly in the phase of the neointima development. Transfection of injured rat carotid arteries with adenoviral vector containing PDGFXR gene nearly completely suppressed activation of PDGF-α receptor and reduced neointima formation. Third, we found that neointimal SMC produced PDGF-B chain in response to angiotensin II (Ang II). Fourth, we demonstrated Ang II activated several molecules, which act as a switch of signal transduction. PDGF-B production via Ras, ERK, JNK, and Egr-1. These results indicate that PDGF-B chain, produced locally by neointimal SMC, plays an essential role in neointima formation after arterial injury. They also suggest the utility of PDGFXR as a therapeutic gene for preventing vascular stenosis after arterial injury.