Vascular Endothelial Growth Factor
Whereas angiogenesis is a common feature in developing skin during embryogenesis, blood vessels in healthy adult skin are quiescent with the exception of the cyclic expansion of perifollicular vessels during the hair cycle. In normal skin, vascular quiescence is maintained by the dominant influence of angiogenesis inhibitors over angiogenic stimuli. The major proangiogenic factor in the skin, vascular endothelial growth factor (VEGF), occurs in at least four isoforms of 121, 165, 189, and 201 amino acid residues. VEGF121 and VEGF165 are the predominant isoforms found in human skin. VEGF mediates its activity mainly through interaction with two type III tyrosine kinase receptors, VEGF receptor-1 (flt-1) and VEGF receptor 2 (KDR, flk-1), which are selectively expressed on the cutaneous endothelium. VEGF-165 also binds the neuropilin receptors on endothelial and other cells. VEGF is expressed at low levels in normal epidermis, whereas keratinocyte VEGF expression is rapidly upregulated by hypoxia and is also induced by several growth factors that mediate epidermal hyperplasia (Figure 1). In psoriasis, healing wounds, and squamous cell carcinomas, transforming growth factor-a and other ligands of the epidermal growth factor receptor are released by suprabasal keratinocytes. In an autocrine loop, these growth factors induce hyperplasia of the epidermis. Simultaneously, they induce VEGF expression and secretion by keratinocytes, leading to paracrine induction of angiogenesis through interaction with VEGF receptors on cutaneous microvessels (Figure 1). This mechanism links epidermal hyperplasia with increased vascularization, thereby providing enhanced vascular support to meet the enhanced nutritional needs of proliferating keratinocytes. Several other growth factors that stimulate keratinocyte proliferation, including keratinocyte growth factor and hepatocyte growth factor/scatter factor, have recently joined the group of molecules that induce keratinocyte VEGF expression.
The biological importance of epidermis-derived VEGF for cutaneous angiogenesis in vivo has been confirmed in transgenic mouse models, using the keratin 14 promoter to selectively target expression of murine VEGF164 to basal epidermal keratinocytes and to follicular keratinocytes of the outer root sheath of the hair follicle. VEGF transgenic
mice are characterized by elongated and tortuous dermal blood vessels that are hyperpermeable for circulating plasma proteins. VEGF overexpressing mice also show enhanced rolling and adhesion of peripheral blood mono-nuclear cells in cutaneous postcapillary venules, suggesting that VEGF also contributes to the recruitment of leukocytes to inflamed skin .
Placental Growth Factor and Other Angiogenic Factors
Placental growth factor (PlGF) is a recently identified new member of the VEGF family that occurs in at least three different isoforms of 149 (PlGF-1), 170 (PlGF-2), and 221 (PlGF-3) amino acids. Both PlGF-1 and PlGF-2 are expressed in human skin. Similar to VEGF, the expression of PlGF is upregulated in cutaneous squamous cell carcinomas, in epidermal keratinocytes at the advancing wound edge, and in the hyperplastic psoriatic epidermis. In contrast to VEGF, PlGF does not activate VEGFR-2 (KDR), but selectively binds to VEGFR-1. In addition, the heparin-binding isoform PlGF-2, but not PlGF-1, binds to the neuropilin receptor. Recent evidence from genetic mouse models indicates that PlGF and VEGF act in synergy to induce skin angiogenesis and vascular leakage, and that the presence of PlGF is essential for distinct VEGF effects to occur . A number of additional proangiogenic molecules are upregulated in angiogenic skin conditions, including interleukin-8, platelet-derived growth factors, and fibroblast growth factors.
Thrombospondin (TSP)-1 and TSP-2 are major endogenous inhibitors of skin angiogenesis and both are expressed in normal human skin. TSP-1 is expressed by dermal cells and by epidermal keratinocytes, and it is deposited in the dermo-epidermal basement membrane zone, contributing to the barrier that prevents ingrowth of blood vessels into the dermis. In contrast, TSP-1 expression is downregulated in squamous cell carcinomas of the skin. Reintroduction of the
TSP-1 gene into squamous cell carcinomas inhibits tumor growth in mice, associated with inhibition of tumor angiogenesis and enhanced tumor cell necrosis. The potential mechanisms by which TSP-1 inhibits skin angiogenesis include the induction of endothelial cell apoptosis through specific interactions with the endothelial CD36 receptor, the activation of latent TGF-beta, and the inhibition of matrix metalloproteinase activity. Overexpression of TSP-1 in the skin of transgenic mice results in impaired granulation tissue formation and wound vascularization  in delayed and reduced skin carcinogenesis, and in diminished photodamage induced by chronic ultraviolet-B irradiation of the skin.
TSP-2 expression during embryonic development and in adult tissues is spatially and temporally different from TSP-1. The expression of TSP-2 is downregulated in epithelial squamous cell carcinoma cells, whereas a strong upregula-tion of TSP-2 is found in the mesenchymal stroma during skin carcinogenesis, representing a natural tumor defense mechanism . Mice that are deficient in TSP-2 show increased skin vascularization, enhanced and prolonged inflammatory reactions, and enhanced skin carcinogenesis, confirming the important role of endogenous TSP-2 in the control of skin angiogenesis. Accordingly, genetic overexpression of TSP-2 protects from skin cancer development and inhibits the growth of established skin cancers. A number of additional endogenous inhibitors of angiogenesis are likely involved in the maintenance of normal vascular quiescence in the skin, including interferons and fragments of collagens type IV, XV, and XVIII. Their potential contribution to the antiangiogenic environment in normal skin remains to be established.
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