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HIF-1 mediated upregulation of VEGF and VEGF-R in systemic sclerosis (SSc): Imbalance with angiostatic factors suggests VEGF as a novel option for the treatment of ischemia in patients with SSc

Vascular changes are consistent early findings in patients with SSc and often precede the development of fibrosis. Despite a significant reduction in the capillary density, there is paradoxically no sufficient angiogenesis in the skin of SSc patients. By using a pO2 histograph, we showed that low pO2 values are overt in involved skin of patients with SSc. In vitro, real-time PCR revealed a 3.7-fold upregulation of the potent angiogenic growth factor VEGF in SSc fibroblasts after hypoxic exposure compared to normoxic controls. In situ hybridization for VEGF in skin biopsies of patients with SSc showed an overexpression of VEGF mRNA by fibroblasts and mononuclear infiltrates, whereas its expression was limited to keratinocytes in healthy control biopsies. In contrast to the SSc skin, HIF-1 alpha protein was found to be coexpressed with VEGF in healthy skin samples, indicating that the constitutive VEGF synthesis in the skin is driven by this transcription factor. Additionally, we showed that the lack of angiogenesis in SSc is not due to a reduced bioavailability of the overexpressed VEGF, since the VEGF receptors Flk-1 and Flt-1 were found to be expressed on endothelial cells of patients with SSc, but not in healthy controls, and since SSc patients had severely elevated serum levels of VEGF compared to healthy controls. Despite the enhanced levels of VEGF, serum samples of SSc patients did not induce angiogen-esis in the vivo chorion allantois membrane assay, indicating that the proangiogenic effects of VEGF may be outweighed by angiostatic factors. The hypothesis that VEGF synthesis has to be above an individual threshold in SSc patients to induce angiogenesis was further strengthened by the finding that patients without fingertip ulcers had significantly higher levels than patients with fingertip ulcers. Interestingly, the angiostatic factor endostatin was elevated in a subset of patients and thus may counteract directly the biologic effects of VEGF in SSc patients. Serum levels of VEGF were also correlated significantly with disease severity parameters including antitopoisomerase antibodies. These results suggest that therapeutic application of VEGF by either gene transfer or as a recombinant protein might be a novel option in SSc.

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  • Hypoxic Exposure
  • Angiogenic Growth Factor
  • Normoxic Control
  • Severity Parameter