Published online before print August 7, 2008

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(American Journal of Pathology. 2008;173:689-699.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080088

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

Peter M. Elias^*, Jack Arbiser, Barbara E. Brown^*, Heidemarie Rossiter, Mao-Qiang Man^*, Francesca Cerimele, Debra Crumrine^*, Roshan Gunathilake^*, Eung Ho Choi^*, Yoshikazu Uchida^*, Erwin Tschachler and Kenneth R. Feingold^*

From the Dermatology^* and Medical Services, Veterans Administration Medical Center and the Department of Dermatology, University of California at San Francisco, San Francisco, California; the Department of Dermatology, Emory School of Medicine, Atlanta, Georgia; and the Department of Dermatology, University of Vienna Medical School, Vienna, Austria

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.