Lille S, Daum G, Clowes M M, Clowes A W
Department of Surgery, University of Washington, Seattle 98195-6410, USA.
J Surg Res. 1997 Jul 1;70(2):178-86. doi: 10.1006/jsre.1997.5114.
Arterial smooth muscle cell (SMC) proliferation is an important factor in the development of atherosclerotic plaques and restenotic lesions following arterial reconstruction. Basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and thrombin are known to induce SMC proliferation and migration in vitro and in vivo. In cultured cells the proliferative responses to these mitogens depend on the activation of the p42/p44 mitogen-activated protein kinases (MAPKs), whereas the role of these kinases in vivo has yet to be established. We tested whether MAPK activity is induced following vessel injury and whether activity is dependent on the release of bFGF, PDGF, and thrombin. Following balloon injury of the left carotid of male Sprague-Dawley rats, arteries were removed and analyzed with respect to MAPK activity, BrdU-labeled nuclei, and/or luminal, medial, and intimal areas. MAPK activity is induced in the rat carotid artery following balloon-catheter injury with a maximum activation at 30 min with a return to just above baseline at 11 hr after injury. Intravenous administration of heparin or neutralizing antibodies to bFGF or PDGF prior to injury reduced SMC proliferation and neointimal lesional formation but did not affect the early induction of MAPK activity. Administration of a tissue factor inhibitor or thrombin inhibitor also did not affect MAPK activity, although it impaired the initiation of the coagulation cascade.
(1) MAPK is activated in a time-dependent manner in response to injury; (2) the antiproliferative effect of heparin in vivo is not mediated through the inhibition of MAPK activity induced 30 min after injury; (3) the activation of MAPK after 30 min is not dependent on PDGF, bFGF, or thrombin following vessel injury in the rat.
动脉平滑肌细胞（SMC）增殖是动脉粥样硬化斑块形成以及动脉重建后再狭窄病变发展的一个重要因素。已知碱性成纤维细胞生长因子（bFGF）、血小板衍生生长因子（PDGF）和凝血酶可在体内外诱导SMC增殖和迁移。在培养细胞中，对这些有丝分裂原的增殖反应取决于p42/p44丝裂原活化蛋白激酶（MAPK）的激活，而这些激酶在体内的作用尚未明确。我们测试了血管损伤后MAPK活性是否被诱导，以及该活性是否依赖于bFGF、PDGF和凝血酶的释放。对雄性Sprague-Dawley大鼠的左颈动脉进行球囊损伤后，取出动脉并分析其MAPK活性、BrdU标记的细胞核以及管腔、中膜和内膜面积。球囊导管损伤后大鼠颈动脉中MAPK活性被诱导，损伤后30分钟激活达到最大值，11小时后恢复到略高于基线水平。损伤前静脉注射肝素或bFGF或PDGF的中和抗体可减少SMC增殖和新生内膜病变形成，但不影响MAPK活性的早期诱导。给予组织因子抑制剂或凝血酶抑制剂也不影响MAPK活性，尽管它会损害凝血级联反应的启动。
（1）MAPK在损伤后以时间依赖性方式被激活；（2）肝素在体内的抗增殖作用不是通过抑制损伤后30分钟诱导的MAPK活性介导的；（3）大鼠血管损伤后30分钟后MAPK的激活不依赖于PDGF、bFGF或凝血酶。
