Bilato C, Pauly R R, Melillo G, Monticone R, Gorelick-Feldman D, Gluzband Y A, Sollott S J, Ziman B, Lakatta E G, Crow M T
Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
J Clin Invest. 1995 Oct;96(4):1905-15. doi: 10.1172/JCI118236.
Intracellular signaling pathways activated by both PDGF and basic fibroblast growth factor (bFGF) have been implicated in the migration of vascular smooth muscle cells (VSMC), a key step in the pathogenesis of many vascular diseases. We demonstrate here that, while bFGF is a weak chemoattractant for VSMCs, it is required for the PDGF-directed migration of VSMCs and the activation of calcium/calmodulin-dependent protein kinase II (CamKinase II), an intracellular event that we have previously shown to be important in the regulation of VSMC migration. Neutralizing antibodies to bFGF caused a dramatic reduction in the size of the intracellular calcium transient normally seen after PDGF stimulation and inhibited both PDGF-directed VSMC migration and CamKinase II activation. Partially restoring the calcium transient with ionomycin restored migration and CamKinase II activation as did the forced expression of a mutant CamKinase II that had been "locked" in the active state by site-directed mutagenesis. These results suggest that bFGF links PDGF receptor stimulation to changes in intracellular calcium and CamKinase II activation, reinforcing the central role played by CamKinase II in regulating VSMC migration.
血小板衍生生长因子（PDGF）和碱性成纤维细胞生长因子（bFGF）激活的细胞内信号通路与血管平滑肌细胞（VSMC）的迁移有关，这是许多血管疾病发病机制中的关键步骤。我们在此证明，虽然bFGF对VSMCs是一种弱化学引诱剂，但它是PDGF引导的VSMCs迁移和钙/钙调蛋白依赖性蛋白激酶II（钙调蛋白激酶II）激活所必需的，我们之前已表明这一细胞内事件在VSMC迁移调节中很重要。针对bFGF的中和抗体导致PDGF刺激后通常所见的细胞内钙瞬变大小显著减小，并抑制了PDGF引导的VSMC迁移和钙调蛋白激酶II激活。用离子霉素部分恢复钙瞬变可恢复迁移和钙调蛋白激酶II激活，通过定点诱变“锁定”在活性状态的突变钙调蛋白激酶II的强制表达也有同样效果。这些结果表明，bFGF将PDGF受体刺激与细胞内钙变化和钙调蛋白激酶II激活联系起来，强化了钙调蛋白激酶II在调节VSMC迁移中所起的核心作用。
