Epidermal vascular endothelial growth factor production is required for permeability barrier homeostasis, dermal angiogenesis, and the development of epidermal hyperplasia - Implications for the pathogenesis of psoriasis
Epidermal vascular endothelial growth factor production is required for permeability barrier homeostasis, dermal angiogenesis, and the development of epidermal hyperplasia - Implications for the pathogenesis of psoriasis
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DOI：
10.2353/ajpath.2008.080088
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发表时间：
2008-09-01
影响因子：
6
通讯作者：
Feingold, Kenneth R.
中科院分区：
文献类型：
--
作者：
Elias, Peter M.;Arbiser, Jack;Feingold, Kenneth R.
渗透性屏障功能的原发性异常似乎是特应性皮炎和表皮创伤的基础;伴随的屏障功能障碍也可能导致其他炎性皮肤病，包括银屑病。这种由外而内的疾病发病机制的核心是表皮产生细胞因子/生长因子，这反过来又发出下游表皮修复机制的信号。然而，这种级联反应，如果持续下去，信号下游表皮增生和炎症。我们发现，急性屏障破坏迅速刺激正常无毛小鼠表皮血管内皮生长因子-A（VEGF-A）的mRNA和蛋白质表达，这是对渗透性屏障要求的特异性反应，因为上调被应用蒸汽不渗透膜阻断。此外，表皮VEGF（-/-）小鼠表现出异常的渗透屏障稳态，这归因于表皮板层体产生的VEGF信号传导减少;真皮毛细血管缺乏，血管渗透性降低;并且响应于重复的胶带剥离既没有血管生成也没有表皮增生（银屑病样增生的模型）。这些结果支持表皮VEGF在维持表皮通透性屏障稳态中的核心作用，以及表皮VEGF产生与真皮血管生成和表皮增生发展之间的联系。由于银屑病通常由外部创伤[同构（Koebner）现象]引起，并与显著的渗透屏障异常、过量VEGF产生、显著的血管生成和表皮增生相关，因此这些结果可能为银屑病的发展提供潜在的由外而内的机制基础。
Primary abnormalities in permeability barrier function appear to underlie atopic dermatitis and epidermal trauma; a concomitant barrier dysfunction could also drive other inflammatory dermatoses, including psoriasis. Central to this outside-inside view of disease pathogenesis is the epidermal generation of cytokines/growth factors, which in turn signal downstream epidermal repair mechanisms. Yet, this cascade, if sustained, signals downstream epidermal hyperplasia and inflammation. We found here that acute barrier disruption rapidly stimulates mRNA and protein expression of epidermal vascular endothelial growth factor-A (VEGF-A) in normal hairless mice, a specific response to permeability barrier requirements because up-regulation is blocked by application of a vapor-impermeable membrane. Moreover, epidermal vegf(-/-) mice display abnormal permeability barrier homeostasis, attributable to decreased VEGF signaling of epidermal lamellar body production; a paucity of dermal capillaries with reduced vascular permeability; and neither angiogenesis nor epidermal hyperplasia in response to repeated tape stripping (a model of psoriasiform hyperplasia). These results support a central role for epidermal VEGF in the maintenance of epidermal permeability barrier homeostasis and a link between epidermal VEGF production and both dermal angiogenesis and the development of epidermal hyperplasia. Because psoriasis is commonly induced by external trauma [isomorphic (Koebner) phenomenon] and is associated with a prominent permeability barrier abnormality, excess VEGF production, prominent angiogenesis, and epidermal hyperplasia, these results could provide a potential outside-inside mechanistic basis for the development of psoriasis.