Inhibition of vascular smooth muscle cell migration by peptide and antibody antagonists of the alpha(v)beta(3) integrin complex is reversed by activated calcium/calmodulin-dependent protein kinase II
Inhibition of vascular smooth muscle cell migration by peptide and antibody antagonists of the alpha(v)beta(3) integrin complex is reversed by activated calcium/calmodulin-dependent protein kinase II
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DOI：
10.1172/jci119582
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发表时间：
1997-08-01
影响因子：
15.9
通讯作者：
Crow, MT
中科院分区：
文献类型：
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作者：
Bilato, C;Curto, KA;Crow, MT
血管平滑肌细胞(VSMCs)的迁移被认为在许多血管疾病的发病机制中起关键作用，并受可溶性生长因子/化学诱导剂以及与细胞外基质的相互作用的调节。我们研究了抗大鼠β3抗体和人α(V)β(3)整合素抗体对VSMCs迁移的影响。整合素抗体以及与玻璃连素受体α(V)β(3)和α(V)β(5)结合的环状RGD多肽都显著抑制了PDGF导向的迁移。这导致肌醇(1，4，5)三磷酸的积累减少和钙/钙调蛋白依赖的蛋白激酶II(CaMKII)的激活，这是先前发现的VSMC迁移中的一个重要调节事件。当细胞内CaMKII活性通过离子载体离子霉素升高细胞内钙水平或感染表达结构性激活的CaMKII基因的复制缺陷重组腺病毒(AdCMV.CKIID3)时，PDGF引导的VSMC在抗整合素抗体和环状RGD多肽存在下的迁移被恢复。在稳定表达成分激活但不是野生型CaMKII的细胞系中也观察到了拯救大鼠VSMC，这些观察确定了整合素α(V)β(3)由外向内信号调节VSMC迁移的关键中间产物。
The migration of vascular smooth muscle cells (VSMCs) is thought to play a key role In the pathogenesis of many vascular diseases and is regulated by soluble growth factors/ chemoattractants as well as interactions with the extracellular matrix. We have studied the effects of antibodies to rat beta 3 and human alpha(v) beta(3) integrins on the migration of VSMCs. Both integrin antibodies as well as cyclic RGD peptides that bind to the vitronectin receptors alpha(v) beta(3) and alpha(v) beta(5) significantly inhibited PDGF-directed migration. This resulted in a reduction in the accumulation of inositol (1,4,5) trisphosphate and the activation of calcium/calmodulin-dependent protein kinase II (CamKII), an important regulatory event in VSMC migration identified previously. PDGF-directed VSMC migration in the presence of the anti-integrin antibodies and cyclic RGD peptides was restored when intracellular CamKII activity was elevated by either raising intracellular calcium levels with the ionophore, ionomycin, or infecting with a replication-defective recombinant adenovirus expressing a constitutively activated CamKII cDNA (AdCMV.CKIID3). Rescue of rat VSMCs was also observed in stably transfected cell lines expressing constitutively activated but not wild-type CamKII, These observations identify a key intermediate in the regulation of VSMC migration by outside-in signaling from the integrin alpha(v) beta(3).