ACTIVITY OF HIF PATHWAY IN EPIDERMIS AS CONTROL FACTOR FOR SKIN VASCULATURE

A.A. Panteleyev(1), L.A. Usakin(1), E.A. Tverye(1), Yu.A. Chikitkina(1), S.G. Rudayk(2), M.A. Paltsev(2, 3)
1-National Research Centre «Kurchatov Institute», Akademika Kurchatova pl., 1, Moscow, 123182, Russian Federation;
2-N.M. Emanuel Institute of Biochemical Physics, Kosygina str., 4, Moscow, 119334, Russian Federation
3-Financial University under the Government of the Russian Federation,
49 Leningradsky Prospekt, GSP-3, Moscow, 125993, Russian Federation
E-mail: a.a.pantel@gmail.com

Introduction. The physiological state of the skin vasculature is largely determined by the influence of environmental factors, including the alteration of the oxygen partial pressure. Obviously, the epidermis, as the surface layer of the skin, should play a key role in controlling signals affecting on functions of the underlying dermis. However, molecular mechanisms of both epidermis interaction with the dermis and influence of the epidermis on the dermal vasculature remain unclear. The aim of the study was to identify the role of Arnt, a key component of HIF (hypoxia induced factor) pathway for angiogenesis in dermis in mammalians. Methods. As an experimental model, we used mice with suppressed expression of the Arnt gene in the epidermis (Arntflox/floxK14-Cre+). Methods of analysis, histology and immunohistochemistry, as well as standard methods for quantifying the level of gene expression were used. Results. The ablation of Arnt protein expression in the mouse epidermis leads to severe disturbances in the vascular network of the dermis, where the Arnt level remains normal. These disorders are similar to effects on the human skin of anticoagulants as well as with manifestations of some genetic diseases of the vascular system. A significant decrease in von Willebrand factor was detected in the endothelium of the dermal blood vessels of Arnt-KO mice. A significant number of dermal vessels simultaneously expressed CD31, a marker of endothelial cells of the circulatory system and a marker of lymphatic endothelial cells - Lyve1 what indicates to serious vascular pathologies and leads to endothelial dysfunction. Thus, our data indicate to the fact that the loss of Arnt in the epidermis activates the aberrant paracrine regulatory pathway responsible for the dermal vasculature phenotype in Arntflox/floxK14-Cre+ mice. Conclusion. The considered significant role of Arnt in the adaptive response to environmental influences and the similarity between the dermal vascular network phenotype in Arntflox/floxK14-Cre+ mice and the specific vascular signs of tumor stroma and psoriatic skin, Arnt-dependent regulatory cascade can be considered as a potential target for the development of new agents for the treatment of skin pathologies sensitive to the environment. Laboratory animals and cell lines with altered activity of the Arnt gene are a promising model for studying the vascular system of skin and may reveal the role of micro- and macro environmental factors in the control of skin vasculature and pathogenesis of skin diseases.
Keywords: 
Arnt, epidermis, dermis, HIF pathway