Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis.

Abstract

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...

Enhanced expression of vascular endothelial growth factor in metastatic melanoma

“…Overexpression of VEGF has been reported in skin disorders that are characterized by angiogenesis and increased vascular permeability (Brown et al, 1995a). VEGF is strongly expressed by epidermal keratinocytes in wound healing and psoriasis, both accompanied by angiogenesis and increased microvascular permeability (Brown et al, 1992;Detmar et al, 1994). In delayed hypersensitivity skin reactions, which are also characterized by microvascular hyperpermeability, in situ hybridization revealed that the mRNAs encoding VEGF were strikingly overexpressed in keratinocytes of the epidermis (Brown et al, 1995b).…”

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

“…6 In adult skin, VEGF expression is almost undetectable under phy- siologic conditions, while its up-regulation occurs in hyperplastic epidermis of healing wounds 7 and psoriatic skin. 8 VEGF is a potent mitogen for dermal microvascular endothelial cells, 9 it is expressed in keratinocytes of healing wounds 10,11 and acts in a paracrine manner on dermal microvessels, leading to increased skin vascularity. 12,13 Recently, the in vivo activity of hVEGF promoter has been shown in wounded transgenic mouse skin.…”

Ablation of microvessels in vivo upon dimerization of iCaspase-9

“…[5][6][7] VEGF and the pro-angiogenic factors described above appear to function primarily at the level of newly formed vessels where they promote survival by repressing endothelial cell apoptosis. 1 There is mounting evidence that conditions that enhance endothelial cell survival contribute to the pathogenesis of angiogenesis-dependent diseases such as cancer, [8][9][10] psoriasis, 11,12 retinopathy of prematurity, 13 and Crohn's disease. 14 Therefore, reduction or disruption of the local …”