Angiogenesis promoted by vascular endothelial growth factor: Regulation through alpha(1)beta(1) and alpha(2)beta(1) integrins
Angiogenesis promoted by vascular endothelial growth factor: Regulation through alpha(1)beta(1) and alpha(2)beta(1) integrins
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DOI：
10.1073/pnas.94.25.13612
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发表时间：
1997-12-09
影响因子：
11.1
通讯作者：
Detmar, M
中科院分区：
文献类型：
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作者：
Senger, DR;Claffey, KP;Detmar, M
血管内皮生长因子，又称血管通透性因子，是肿瘤和其他病理相关血管生成的重要细胞因子，由于血管生成通常涉及内皮细胞在富含胶原的细胞外基质内的迁移和增殖，我们研究了血管内皮生长因子通过调节胶原受体的表达来促进新生血管的可能性，血管内皮生长因子通过诱导编码α(1)和α(2)亚单位的mRNAs诱导两种胶原受体-α(1)β(1)和α(2)β(1)整合素的表达增加5-7倍。α(3)β(1)整合素也参与胶原结合，整合素α(1)阻断和α(2)阻断抗体均部分抑制微血管BC与I型胶原的附着，抗封闭抗体也抑制IV型胶原和层粘连蛋白-L的附着。血管内皮细胞生长因子诱导α(1)β(1)和α(2)β(1)的表达可促进细胞在I型胶原凝胶上的铺展，而I型胶原凝胶可被α(1)封闭抗体和封闭抗体联合阻断。在体外，α(1)阻断剂和α(2)阻断剂的联合使用显著抑制了血管生成；单个新血管的平均横截面积减少了90%，平均新血管总面积减少了82%，而对原有的血管系统没有明显的影响。这些数据表明，EC诱导α(1)β(1)和α(2)β(1)的表达是促进血管生成的重要机制，α(1)β(1)和α(2)β(1)拮抗剂可能被证明在癌症和其他重要病理中抑制血管生成。
Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, is a cytokine of central importance for the angiogenesis associated with cancers and other pathologies, Because angiogenesis often involves endothelial cell (EC) migration and proliferation within a collagen-rich extracellular matrix, we investigated the possibility that VEGF promotes neovascularization through regulation of collagen receptor expression, VEGF induced a 5- to 7-fold increase in dermal microvascular EC surface protein expression of two collagen receptors-the alpha(1) beta(1) and alpha(2) beta(1) integrins-through induction of mRNAs encoding the alpha(1) and alpha(2) subunits, In contrast, VEGF did not induce increased expression of the alpha(3) beta(1) integrin, which also has been implicated in collagen binding, Integrin alpha(1)-blocking and alpha(2)-blocking antibodies (Ab) each partially inhibited attachment of microvascular BC to collagen I, and anti-blocking Ab also inhibited attachment to collagen IV and laminin-l. Induction of alpha(1) beta(1) and alpha(2) beta(1) expression by VEGF promoted cell spreading on collagen I gels which mas abolished by a combination of alpha(1)-blocking and a blocking Abs. In vitro, a combination of alpha(1)-blocking and alpha(2)-blocking hhs markedly inhibited VEGF-driven angiogenesis; average cross-sectional area of individual new blood vessels was reduced 90% and average total new vascular area was reduced 82% without detectable effects on the pre-existing vasculature, These data indicate that induction of alpha(1) beta(1) and alpha(2) beta(1) expression by the EC is an important mechanism by which VEGF promotes angiogenesis and that alpha(1) beta(1) and alpha(2) beta(1) antagonists may prove effective in inhibiting VEGF-driven angiogenesis in cancers and other important pathologies.