Upregulation of hypoxia-inducible factors in normal and psoriatic skin

Angiogenesis induced by vascular endothelial growth factor ( VEGF) plays an important role in psoriasis. Hypoxic adaptation is conferred through hypoxia- inducible transcription factors ( HIFs). VEGF and its receptor Flt- 1 are HIF target genes. Growth factors and inflammatory cytokines activate the phosphoinositol- 3 kinase pathway, and via activated protein kinase B ( phospho- Akt) augment HIF activity. Here, we demonstrate that the major oxygen- dependent HIF isoforms are strongly upregulated in psoriatic skin: HIF- 1 alpha mainly in the epidermis, in an expression pattern similar to VEGF mRNA; HIF- 2 alpha in both the epidermis and in capillary endothelial cells of the dermis. In contrast, normal human skin shows low expression of HIF-alpha proteins, with the exception of hair follicles, and glands, which strongly express HIF- 1 alpha. In normal human skin, phospho- Akt appeared in the basal epidermal layer, in hair follicles, and in dermal glands. In contrast, in psoriasis, phospho-Akt expression was low in the epidermis, but markedly enhanced in the dermal capillaries and in surrounding interstitial/ inflammatory cells. Our data suggest that hypoxia initiates a potentially self- perpetuating cycle involving HIF, VEGF, and Akt activation, which could drive physiologic growth of hair follicles and skin glands. Furthermore, such a cycle may exist in psoriasis in dermal capillaries and contribute to disease progression.