Impaired wound repair and delayed angiogenesis in aged mice.
Wound repair is a multistep process consisting of hemostasis, inflammatory cell infiltration, tissue regrowth, and remodeling. In aged individuals, this progression of events is altered, resulting in wounds that heal more slowly than wounds in the young. These studies were designed to examine the proliferative phase of repair in young and aged mice, with attention to the angiogenic process. Using a standardized excisional injury model, wound re-epithelialization, collagen accumulation, and angiogenesis were examined. Re-epithelialization and collagen synthesis were substantially delayed in aged mice as compared with young mice. Angiogenesis in wounds from aged mice was also delayed, with significantly more capillary growth in wounds from young mice than aged mice. In addition, wounds from aged mice contained significantly less of the angiogenic mediators fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF) than wounds from young animals (p < 0.05). Because macrophages are a rich source of angiogenic factors in wounds, macrophage production of VEGF was examined. Macrophages from aged mice produced significantly less VEGF than cells from young mice. To examine the in vivo endothelial cell responsiveness, a defined amount of rFGF-2 was suspended in Matrigel and placed subcutaneously in either young or aged mice. In response to FGF-2, capillary growth into Matrigel was significantly less in aged than young mice. The results suggest that a decline in angiogenic growth factor production, as well as a decline in endothelial responsiveness to specific factors, may account for the delayed wound angiogenesis in aged mice. These results also indicate that age-related alterations in macrophage function might partially account for the overall delay in the wound repair process.
Swift
M E
ME
Department of Microbiology and Immunology, Burn and Shock Trauma Institute, Loyola University Medical Center, Maywood, Illinois 60153, USA.
Kleinman
H K
HK
DiPietro
L A
LA
D000375:Aging / Q000502:physiology*; D000818:Animals; D003094:Collagen / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D008222:Lymphokines / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018919:Neovascularization, Physiologic; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014945:Wound Healing
D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D003094:Collagen