Retroviral delivery of dominant-negative vascular endothelial growth factor receptor type 2 to murine wounds inhibits wound angiogenesis.
Vascular endothelial growth factor (VEGF) is a potent paracrine signal for initiating angiogenesis. Although VEGF can bind to several cell surface receptors, VEGF receptor type 2 (VEGFR2, a.k.a. KDR or flk-1) is the primary receptor responsible for VEGF-induced endothelial cell proliferation. To determine whether the VEGF-VEGFR2 signaling axis has an important role in wound healing angiogenesis, we used a retrovirus to deliver a signaling-defective truncated VEGFR2 (tm VEGFR2) to block VEGF-VEGFR2-induced endothelial cell proliferation in murine wounds. We show that the retroviral construct effectively blocked phosphorylation of VEGFR2 in vitro and we were able to express the truncated receptor in murine wounds. We achieved significant reduction of angiogenesis and granulation tissue formation in murine wounds, but this did not lead to delayed wound closure. In contrast, there was a corresponding increase in wound contraction, showing that functional VEGFR2 intracellular signaling is not critical for normal closure of excisional dermal wounds. Our results show a novel relationship between wound bed vascularity and wound contraction.
Department of Surgery, VA Puget Sound Health Care System and University of Washington Medical Center, Seattle, Washington 98195, USA. isik@u.washington.edu
Raymond
R
Tsou
Carrie
C
Fathke
Lynne
L
Wilson
Ken
K
Wallace
Nicole
N
Gibran
Frank
F
Isik
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D005822:Genetic Vectors; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology*; D012190:Retroviridae; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000008:administration & dosage* / Q000502:physiology*; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology*; D014950:Wounds, Penetrating / Q000503:physiopathology*
D040301:Vascular Endothelial Growth Factor Receptor-2