Systemic sclerosis (SSc) is characterized by autoimmunity, small vessel pathology and tissue fibrosis. Several studies have shown decreased oxygen levels in the skin of patients with SSc. This is caused by a reduced capillary density which together with the proliferative vasculopathy of small arteries and possibly large vessel pathology leads to decreased blood flow and impaired tissue oxygenation. Oxygen supply is further reduced by the accumulation of extracellular matrix (ECM), which increases diffusion distances from blood vessels to cells. Recent years have shown that hypoxia is not an innocent bystander, but contributes independently to the pathophysiology of SSc. For example, hypoxia stimulates the production of ECM proteins in a transforming growth factor-beta-dependent manner. There are inconsistent results in how far hypoxia-inducible factor-1alpha-dependent pathways contribute to fibroblast-mediated ECM accumulation. Hypoxia may also perpetuate the microvasculopathy characteristic for SSc by interfering with vascular endothelial growth factor (VEGF) receptor signalling. Hypoxia is a well characterized inducer of VEGF and may cause chronic VEGF over-expression in SSc. Uncontrolled over-expression of VEGF has been shown to have negative rather than stimulatory effects on angiogenesis leading to the formation of chaotic, sac-like capillaries with decreased blood flow. While attacks from Raynaud's phenomenon are probably too short to induce HIF-1 alpha dependent pathways, they can contribute to the SSc pathogenesis by inducing ischemia-reperfusion events with increased oxidative stress. Taken together, hypoxia might play a central role in pathogenesis of SSc by augmenting microvascular disease and tissue fibrosis.
Disclosure of Interest None declared