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 .

Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a multifunctional cytokine expressed and secreted at high levels by many tumor cells of animal and human origin. As secreted by tumor cells, VPF/VEGF is a 34-42 kDa heparin-binding, dimeric, disulfide-bonded glycoprotein that acts directly on endothelial cells (EC) by way of specific receptors to activate phospholipase C and induce [Ca2+]i transients. Two high affinity VPF/VEGF receptors, both tyrosine kinases, have thus far been described. VPF/VEGF is likely to have a number of important roles in tumor biology related, but not limited to, the process of tumor angiogenesis. As a potent permeability factor, VPF/VEGF promotes extravasation of plasma fibrinogen, leading to fibrin deposition which alters the tumor extracellular matrix. This matrix promotes the ingrowth of macrophages, fibroblasts, and endothelial cells. Moreover, VPF/VEGF is a selective endothelial cell (EC) growth factor in vitro, and it presumably stimulates EC proliferation in vivo. Furthermore, VPF/VEGF has been found in animal and human tumor effusions by immunoassay and by functional assays and very likely accounts for the induction of malignant ascites. In addition to its role in tumors, VPF/VEGF has recently been found to have a role in wound healing and its expression by activated macrophages suggests that it probably also participates in certain types of chronic inflammation. VPF/VEGF is expressed in normal development and in certain normal adult organs, notably kidney, heart, adrenal gland and lung. Its functions in normal adult tissues are under investigation.

SummaryPsoriatic skin is characterized by microvascular hyperpermeability and angioproliferation, but the mechanisms responsible are unknown. We report here that the hyperplastic epidermis of psoriatic skin expresses strikingly increased amounts of vascular permeability factor (VPF; vascular endothelial growth factor), a selective endothelial cell mitogen that enhances microvascular permeability. Moreover, two VPF receptors, kdr and fit-l, are overexpressed by papillary dermal microvascular endothelial cells. Transforming growth factor ot (TGF-o 0, a cytokine that is also overexpressed in psoriatic epidermis, induced VPF gene expression by cultured epidermal keratinocytes. VPF secreted by TGF-c~-stimulated keratinocytes was bioactive, as demonstrated by its mitogenic effect on dermal microvascular endothelial cells in vitro. Together, these findings suggest that TGF-ot regulates VPF expression in psoriasis by an autocrine mechanism, leading to vascular hyperpermeability and angiogenesis. Similar mechanisms may operate in tumors and in healing skin wounds which also commonly express both VPF and TGF-ol. p! soriasis is a common, chronic skin disease characterized by recurrent erythematous skin plaques that exhibit epidermal hyperplasia, a variable inflammatory cell infiltrate, and abnormalities of the papillary dermal vasculature (1-4). Microvessels in the papillary dermis of psoriatic plaques are elongate, dilated, and hyperpermeable (5, 6) and more closely resemble postcapillary venules than the capillary loops of normal skin (7,8). Whereas vascular changes may precede inflammatory cell infiltration in developing psoriatic plaques, and may reappear before clinical relapse (9-11), there is increasing evidence that epidermal alterations precede capillary leakiness and vascular anomalies in the development of psoriatic skin lesions (12). Moreover, a previous study demonstrated that the angiogenic properties of psoriatic skin were associated with the epidermis, not the dermis (13).Vascular permeability factor (VPF) is a 32-42-kD glycosylated protein that is overexpressed by many human and animal tumors (14-17) and by the epidermis of healing wounds (18), conditions that, like psoriasis, are associated with enhanced microvascular permeability and angiogenesis. Two tyrosine kinase receptors for VPF, kdr and fit-l, are also overexpressed in the microvessels of tumors that overexpress VPF (19)(20)(21). In vivo, VPF enhances microvascular permeability with a potency some 50,000 times that of histamine and induces angiogenesis (22)(23)(24)(25). In vitro, VPF is a selective mitogen for cultured endothelial cells, hence its alternate name, vascular endothelial growth factor (26, 27). We hypothesized that a cytokine with these properties might play an important role in the pathogenesis of psoriasis.In this report, we demonstrate increased expression of VPF mRNA by the hyperplastic epidermis of lesional psoriatic skin and increased expression of two VPF receptors in psoriatic dermal microvessels. In vitro investigations showe...