VEGF‐A promotes tissue repair‐associated lymphatic vessel formation via VEGFR‐2 and the α1β1 and α2β1 integrins

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Abstract
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 α1 and α2 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‐α1 and anti‐α2 integrin blocking antibodies, and systemic blockade of the α1 and α2 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.
Funding Information
  • Deutsche Forschungsgemeinschaft