Thrombospondin-1 suppresses wound healing and granulation tissue formationin the skin of transgenic mice

The function of the endogenous angiogenesis inhibitor thrombospondin-1 (TSP -1) in tissue repair has remained controversial. We established transgenic mice with targeted overexpression of TSP-1 in the skin, using a keratin 14 expression cassette. TSP-1 transgenic mice were healthy and fertile, and di d not show any major abnormalities of normal skin vascularity, cutaneous va scular architecture, or microvascular permeability. However, healing of ful l-thickness skin wounds was greatly delayed in TSP-1 transgenic mice and wa s associated with reduced granulation tissue formation and highly diminishe d wound angiogenesis, Moreover, TSP-1 potently inhibited fibroblast migrati on in vivo and in vitro. These findings demonstrate that TSP-1 preferential ly interfered with wound healing-associated angiogenesis, rather than with the angiogenesis associated with normal development and skin homeostasis, a nd suggest that therapeutic application of angiogenesis inhibitors might po tentially be associated with impaired wound vascularization and tissue repa ir.