title: Time course analysis of hypoxia, granulation tissue and blood vessel growth, and remodeling in healing rat cutaneous incisional primary intention wounds.
abstract: Hypoxia and the development and remodeling of blood vessels and connective tissue in granulation tissue that forms in a wound gap following full-thickness skin incision in the rat were examined as a function of time. A 1.5 cm-long incisional wound was created in rat groin skin and the opposed edges sutured together. Wounds were harvested between 3 days and 16 weeks and hypoxia, percent vascular volume, cell proliferation and apoptosis, alpha-smooth muscle actin, vascular endothelial growth factor-A, vascular endothelial growth factor receptor-2, and transforming growth factor-beta1 expression in granulation tissue were then assessed. Hypoxia was evident between 3 and 7 days while maximal cell proliferation at 3 days (123.6+/-22.2 cells/mm2, p<0.001 when compared with normal skin) preceded the peak percent vascular volume that occurred at 7 days (15.83+/-1.10%, p<0.001 when compared with normal skin). The peak in cell apoptosis occurred at 3 weeks (12.1+/-1.3 cells/mm2, p<0.001 when compared with normal skin). Intense alpha-smooth muscle actin labeling in myofibroblasts was evident at 7 and 10 days. Vascular endothelial growth factor receptor-2 and vascular endothelial growth factor-A were detectable until 2 and 3 weeks, respectively, while transforming growth factor-beta1 protein was detectable in endothelial cells and myofibroblasts until 3-4 weeks and in the extracellular matrix for 16 weeks. Incisional wound granulation tissue largely developed within 3-7 days in the presence of hypoxia. Remodeling, marked by a decline in the percent vascular volume and increased cellular apoptosis, occurred largely in the absence of detectable hypoxia. The expression of vascular endothelial growth factor-A, vascular endothelial growth factor receptor-2, and transforming growth factor-beta1 is evident prior, during, and after the peak of vascular volume reflecting multiple roles for these factors during wound healing.
authors.affiliation: Bernard O'Brien Institute of Microsurgery and University of Melbourne Department of Surgery, St. Vincent's Hospital, Melbourne, Australia.
authors.forename: Zerina
authors.initials: Z
authors.lastname: Lokmic
authors.forename: Ian A
authors.initials: IA
authors.lastname: Darby
authors.forename: Erik W
authors.initials: EW
authors.lastname: Thompson
authors.forename: Geraldine M
authors.initials: GM
authors.lastname: Mitchell
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D015687:Cell Hypoxia; D006097:Granulation Tissue / Q000098:blood supply* / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000098:blood supply / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*
chemical_list: D000199:Actins; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D010100:Oxygen