Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing.

Abstract

SummaryPersistent microvascular hyperpermeability to plasma proteins even after the cessation of injury is a characteristic but poorly understood feature of normal wound healing. It results in extravasation of fibrinogen that clots to form fibrin, which serves as a provisional matrix and promotes angiogenesis and scar formation. We present evidence indicating that vascular permeability factor (VPF ; also known as vascular endothelial growth factor) may be responsible for the hyperpermeable state, as well as the angiogenesis, that are characteristic of healing wounds . Hyperpermeable blood vessels were identified in healing split-thickness guinea pig and rat punch biopsy skin wounds by their capacity to extravasate circulating macromolecular tracers (colloidal carbon, fluoresceinated dextran) . Vascular permeability was maximal at 2-3 d, but persisted as late as 7 d after wounding . Leaky vessels were found initially at the wound edges and later in the subepidermal granulation tissue as keratinocytes migrated to cover the denuded wound surface. Angiogenesis was also prominent within this 7-d interval . In situ hybridization revealed that greatly increased amounts of VPF mRNA were expressed by keratinocytes, initially those at the wound edge, and, at later intervals, keratinocytes that migrated to cover the wound surface; occasional mononuclear cells also expressed VPF mRNA . Secreted VPF was detected by immunofluoroassay of medium from cultured human keratinocytes. These data identify keratinocytes as an important source of VPF gene transcript and protein, correlate VPF expression with persistent vascular hyperpermeability and angiogenesis, and suggest that VPF is an important cytokine in wound healing .

Recombinant AAV vector encoding human VEGF165 enhances wound healing

“…38 Elevated VEGF mRNA levels were found in keratinocytes at the wound edges and in keratinocytes that migrate to cover the wound surface. 10 Occasional mononuclear cells, probably macrophages, in the wound bed also express VEGF. Moreover, antibody neutralization of this cytokine was demonstrated to inhibit formation of wound granulation tissue.…”

“…DOI: 10.1038/sj/gt/3301697 angiogenic growth factors from macrophages and keratinocytes and its impairment leads to a delay in skin repair. [7][8][9][10][11] One of the essential growth factors which are involved in the angiogenetic process in the wounded tissues is vascular endothelial growth factor (VEGF), 12 which promotes proliferation and migration of endothelial cells resulting in the formation of a capillary network which is an essential requisite for the healing process.…”

Current approaches and perspectives in human keratinocyte-based gene therapies

“…Keratinocytes upregulate the expression of numerous cytokines that appear to contribute to tissue repair during normal wound healing. 36,37 However, seriously damaged dermal tissue may not efficiently sense the stimulus provided by grafted keratinocytes. If a burned area is covered by keratinocytes overexpressing either a particular or various healing-promoting factor(s), in situ conditioning of the damaged dermal bed may occur.…”

Adenovirus-mediated VEGF165 gene transfer enhances wound healing by promoting angiogenesis in CD1 diabetic mice

“…29,30 The expression of VEGF and VEGF receptors is upregulated, during the normal wound healing process, in migrating keratinocytes, 31,32 in sprouting blood vessels at the wound edge and in the granulation tissue. VEGF production is stimulated during this process, besides by hypoxia, by key molecules such as epidermal growth factor (EGF) family members, keratinocyte growth factor (KGF) and transforming growth factor-␤1 (TGF-␤1) 11 accumulating at the wound site.…”