title: Transgenic overexpression of keratinocyte-specific VEGF and Ang1 in combination promotes wound healing under nondiabetic but not diabetic conditions.
abstract: VEGF and Angiopoietin (Ang)1 are growth factors that independently improve wound healing outcomes. Using a tet-repressible mouse model coupled with streptozotocin-induced diabetes, we examined wound healing in diabetic and nondiabetic mice engineered to overexpress keratinocyte-specific (K5) VEGF, Ang1 or Ang1-VEGF combined. All nondiabetic mice healed more rapidly than their diabetic counterparts; however overexpression of VEGF, Ang1 or the combination failed to improve wound closure under diabetic conditions. Conversely, under nondiabetic conditions, combining Ang1 and VEGF resulted in rapid wound closure. Molecular analyses of diabetic and nondiabetic K5-Ang1-VEGF skin revealed no differences in VEGF expression but an 80% decrease in Ang1 under diabetic conditions, suggesting an integral role for Ang1. Nondiabetic K5-Ang1 mice healed more quickly and had significant increases in granulation tissue and a 60% decrease in re-epithelialization 7 days after wounding. Furthermore, Ang1 stimulated primary mouse keratinocytes showed significantly less migration into a wound bed in an in vitro wound healing bioassay and had decreased pMAPK, pNFκB, pAkt, and pStat3 signaling. These data suggest that combined Ang1-VEGF overexpression cannot overcome diabetes-induced delays in wound healing but is efficacious under nondiabetic conditions possibly via Ang1-mediated delays in re-epithelialization and enhancement of granulation tissue formation, thereby allowing more rapid secondary intention healing.
authors.affiliation: Department of Dermatology, Case Western Reserve University Cleveland, OH 44106, USA.
authors.forename: Candace M
authors.initials: CM
authors.lastname: Loyd
authors.forename: Doina
authors.initials: D
authors.lastname: Diaconu
authors.forename: Wen
authors.initials: W
authors.lastname: Fu
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Adams
authors.forename: Erin
authors.initials: E
authors.lastname: Brandt
authors.forename: Dorothy A
authors.initials: DA
authors.lastname: Knutsen
authors.forename: Julie A
authors.initials: JA
authors.lastname: Wolfram
authors.forename: Thomas S
authors.initials: TS
authors.lastname: McCormick
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Ward
mesh_terms: D042683:Angiopoietin-1 / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D004797:Enzyme-Linked Immunosorbent Assay; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics; D014945:Wound Healing / Q000502:physiology*
chemical_list: D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse