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-1alpha mainly in the epidermis, in an expression pattern similar to VEGF mRNA; HIF-2alpha 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-1alpha. 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.
Rosenberger
Christian
C
Nephrology and Medical Intensive Care, Charité Universitätsmedizin, Virchow Campus, Berlin, Germany. chrosenbe@aol.com
Solovan
Caius
C
Rosenberger
Alina D
AD
Jinping
Li
L
Treudler
Regina
R
Frei
Ulrich
U
Eckardt
Kai-Uwe
KU
Brown
Lawrence F
LF
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001706:Biopsy; D015687:Cell Hypoxia; D018450:Disease Progression; D025461:Feedback, Physiological; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D011565:Psoriasis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051058:Oncogene Protein v-akt; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C497444:Hif1a protein, rat; C501162:FLT1 protein, human