VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1beta1 and alpha2beta1 integrins.
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.
Hong
Young-Kwon
YK
Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Lange-Asschenfeldt
Bernhard
B
Velasco
Paula
P
Hirakawa
Satoshi
S
Kunstfeld
Rainer
R
Brown
Lawrence F
LF
Bohlen
Peter
P
Senger
Donald R
DR
Detmar
Michael
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D019070:Cell Lineage; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D039423:Integrin alpha1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D039421:Integrin alpha2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D053547:Keratin-14; D007633:Keratins / Q000235:genetics; D042583:Lymphangiogenesis / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000502:physiology*; D012867:Skin / Q000293:injuries; D015854:Up-Regulation / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology*
D000911:Antibodies, Monoclonal; D039423:Integrin alpha1; D039421:Integrin alpha2; C507540:KRT14 protein, human; D053547:Keratin-14; C507446:Krt14 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D007633:Keratins; D040301:Vascular Endothelial Growth Factor Receptor-2