Discordant effects of a soluble VEGF receptor on wound healing and angiogenesis

Abstract

Soluble receptors to vascular endothelial growth factor (VEGF) can inhibit its angiogenic effect. Since angiogenesis is involved in wound repair, we hypothesized that adenovirus-mediated gene transfer of a soluble form of VEGF receptor 2 (Flk-1) would attenuate wound healing in mice. C57Bl/6J and genetically diabetic (db/db) mice (each n¼20) received intravenous (i.v.) injections of recombinant adenoviruses (10 9 PFU) encoding the ligand-binding ectodomain of VEGF receptor 2 (Flk-1) or cDNA encoding the murine IgG2a Fc fragment (each n¼10). At 4 days after gene transfer, two full-thickness skin wounds (0.8 cm) were created on the dorsum of each animal. Wound closure was measured over 9-14 days after which wounds were resected for histological analysis. Prior to killing, fluorescent microspheres were systemically injected for quantitation of wound vascularity. Single i.v. injections of adenoviruses encoding soluble Flk-1 significantly decreased wound angiogenesis in both wild-type and diabetic mice. Fluorescence microscopy revealed a 2.0-fold (wild type) and 2.9-fold (diabetic) reduction in wound vascularity in Flk-1-treated animals (po0.05). Impairment of angiogenesis was confirmed by CD31 immunohistochemistry. Interestingly, despite significant reductions in wound vascularity, wound closure was not grossly delayed. Our data indicates that while VEGF function is essential for optimal wound angiogenesis, it is not required for wound closure.

Regulation of scar formation by vascular endothelial growth factor

“…[34][35][36][37] The benefits of enhanced angiogenesis have primarily been shown in models of impaired wound healing 28,32,33 or severe injury. [29][30][31] In contrast, several reports have shown that modulation of angiogenesis does not affect epidermal healing rates or overall wound closure to a great degree, [38][39][40][41][42][43] and some studies have even reported enhanced healing with reduced angiogenesis. 44 Thus, although there are many studies examining angiogenesis and wound repair, the degree to which angiogenesis actually facilitates healing under normal circumstances is still not known.…”

Innate Immunity and Angiogenesis

“…Interestingly, the Ϸ10% of Net ␦/d mice that survive development (and were used for these experiments) exhibited normal development of the vascular tree but had abnormalities in lymphatic development. 29 Despite the central role of VEGFs in cutaneous wound repair, Jacobi et al 30 noted that a single intravenous injection of an adenoviral-delivered transgene, encoding a soluble form of VEGF-R 2 (ie, Flk-1), acting as a "VEGF-trap," reduced skin wound-related angiogenesis but did not affect the rate of wound closure in either db/db diabetic or wild-type animals (although, as expected, wound closure in diabetic animals was slower than in wild-type animals, with or without the VEGF-trap construct). This result was also observed in other in vivo wound repair models in which angiogenesis was selectively impaired.…”

Neurovascular Factors in Wound Healing in the Foot Skin of Type 2 Diabetic Subjects

“…Furthermore, topical application of VEGF or overexpression of VEGF by an adenoviral vector markedly accelerates wound healing in diabetic animals (17,25). While adenovirus-mediated gene transfer of a soluble form of VEGFR-2 (Flk-1) reduces angiogenesis, it does not delay wound closure in db/db mice (26). Although tissue hypoxia, a typical feature of healing wounds, is thought to increase the expression of VEGF through HIF-1␣ (27), the role of HIF-1␣ in diabetic wounds has not been explored in experimental studies and in particular in diabetic patients.…”