VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the α1β1 and α2β1 integrins
VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the α1β1 and α2β1 integrins
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DOI：
10.1096/fj.03-1179fje
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发表时间：
2004-05-01
期刊：
影响因子：
4.8
通讯作者：
Detmar, M
中科院分区：
文献类型：
--
作者：
Hong, YK;Lange-Asschenfeldt, B;Detmar, M
血管内皮生长因子-A（VEGF-A）在受伤的皮肤组织中强烈上调，并促进修复相关的血管生成。然而，很少有人知道它在愈合皮肤的淋巴再生中的作用。我们研究了在表皮特异性过表达VEGF-A的转基因小鼠和在VEGF-A信号传导抑制剂存在或不存在的野生型小鼠中的伤口愈合。令人惊讶的是，皮肤中VEGF-A的转基因过表达促进了伤口愈合部位的淋巴管生成，而VEGFR-2的全身阻断阻止了淋巴管形成。在培养的淋巴管内皮细胞的研究表明，VEGF-A诱导α 1和α 2整合素的表达，这促进了他们在体外管的形成和他们的haptotactic迁移向I型胶原蛋白。VEGF-A诱导的淋巴管内皮索形成和趋触性迁移被抗α 1和抗α 2整合素阻断抗体抑制，并且α 1和α 2整合素的全身阻断抑制VEGF-A驱动的体内淋巴管生成。我们认为VEGF-A通过激活VEGFR-2促进淋巴管形成，并且整合素受体表达的谱系特异性差异有助于伤口相关血管生成和淋巴管生成的独特动力学。
Vascular endothelial growth factor-A (VEGF-A) is strongly up-regulated in wounded cutaneous tissue and promotes repair-associated angiogenesis. However, little is known about its role in lymphatic regeneration of the healing skin. We studied wound healing in transgenic mice that overexpress VEGF-A specifically in the epidermis and in wild-type mice in the absence or presence of inhibitors of VEGF-A signaling. Surprisingly, transgenic overexpression of VEGF-A in the skin promoted lymphangiogenesis at the wound healing site, whereas systemic blockade of VEGFR-2 prevented lymphatic vessel formation. Studies in cultured lymphatic endothelial cells revealed that VEGF-A induced expression of the alpha1 and alpha2 integrins, which promoted their in vitro tube formation and their haptotactic migration toward type I collagen. VEGF-A-induced lymphatic endothelial cord formation and haptotactic migration were suppressed by anti-alpha1 and anti-alpha2 integrin blocking antibodies, and systemic blockade of the alpha1 and alpha2 integrins inhibited VEGF-A-driven lymphangiogenesis in vivo. We propose that VEGF-A promotes lymphatic vasculature formation via activation of VEGFR-2 and that lineage-specific differences of integrin receptor expression contribute to the distinct dynamics of wound-associated angiogenesis and lymphangiogenesis.