Loss of vascular endothelial growth factor a activity in murine epidermal keratinocytes delays wound healing and inhibits tumor formation.
The angiogenic cytokine vascular endothelial growth factor (VEGF)-A plays a central role in both wound healing and tumor growth. In the skin, epidermal keratinocytes are a major source of this growth factor. To study the contribution of keratinocyte-derived VEGF-A to these angiogenesis-dependent processes, we generated mice in which this cytokine was inactivated specifically in keratin 5-expressing tissues. The mutant mice were macroscopically normal, and the skin capillary system was well established, demonstrating that keratinocyte-derived VEGF-A is not essential for angiogenesis in the skin during embryonic development. However, healing of full-thickness wounds in adult animals was appreciably delayed compared with controls, with retarded crust shedding and the appearance of a blood vessel-free zone underneath the newly formed epidermis. When 9,12-dimethyl 1,2-benzanthracene was applied as both tumor initiator and promoter, a total of 143 papillomas developed in 20 of 23 (87%) of control mice. In contrast, only three papillomas arose in 2 of 17 (12%) of the mutant mice, whereas the rest merely displayed epidermal thickening and parakeratosis. Mutant mice also developed only 2 squamous cell carcinomas, whereas 11 carcinomas were found in seven of the control animals. These data demonstrate that whereas keratinocyte-derived VEGF-A is dispensable for skin vascularization under physiological conditions, it plays an important albeit nonessential role during epidermal wound healing and is crucial for the development of 9,12-dimethyl 1,2-benzanthracene-induced epithelial skin tumors.
Rossiter
Heidemarie
H
Department of Dermatology, Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria.
Barresi
Caterina
C
Pammer
Johannes
J
Rendl
Michael
M
Haigh
Jody
J
Wagner
Erwin F
EF
Tschachler
Erwin
E
D000818:Animals; D005091:Exons; D015603:Keratinocytes / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D010212:Papilloma / Q000098:blood supply* / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D012867:Skin / Q000098:blood supply / Q000166:cytology; D012878:Skin Neoplasms / Q000098:blood supply* / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*
D042461:Vascular Endothelial Growth Factor A