Upregulation of VEGF expression is associated with accumulation of HIF-1 alpha in the skin of naive scleroderma patients

Abstract

Systemic sclerosis is a disease hallmarked by microangiopathy; the enlargement and leakage of skin capillaries in active stages develops into extensive avascular areas, clinically associated with severe tissue hypoxia and the formation of digital ulcers. Vascular endothelial growth factor (VEGF) is upregulated in all stages of the disease, with little effect on efficient neovascularization. The oxygen-regulated alpha-subunit of hypoxia-inducible transcription factor-1 (HIF-1 alpha) represents a key mechanism involved in the transcriptional regulation of VEGF. The aim of this study is to investigate expression of the oxygen-regulated alpha-subunit of HIF-1 and VEGF in naive scleroderma patients. For this purpose, skin biopsies (dorsal hand surface) from scleroderma patients were analyzed and compared with control skin biopsies. Immunoreactivity for VEGF was enhanced in scleroderma patients, in contrast to restricted positive immunostaining in suprabasal keratinocytes observed in normal skin. In a similar fashion, all skin biopsies from scleroderma patients were strongly HIF-1 alpha reactive, compared with rare immunoreactivity observed in normal skin. The pattern was similar in all stages of scleroderma. These observations for the first time directly connect constitutive hypoxia with VEGF upregulation in scleroderma patients. The sequence of events needs to be precisely mapped, and the pro- and antiangiogenic switches which may interfere with efficient tissue neovascularization identified, in order to provide meaningful therapeutic strategies.