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Rationale: Systemic sclerosis (SSc) is characterized by widespread microangiopathy, fibrosis, and autoimmunity. Despite the lack of angiogenesis, the expression of vascular endothelial growth factor A (VEGF) was shown to be upregulated in SSc skin and circulation; however, previous studies did not distinguish between proangiogenic VEGF165 and antiangiogenic VEGF165 b isoforms, which are generated by alternative splicing in the terminal exon of VEGF pre-RNA.Objective: We investigated whether VEGF isoform expression could be altered in skin and circulation of patients with SSc. Methods and Results: Here, we show that the endogenous antiangiogenic VEGF165 b splice variant is selectively overexpressed at both the mRNA and protein levels in SSc skin. Elevated VEGF165 b expression correlated with increased expression of profibrotic transforming growth factor-β1 and serine/arginine protein 55 splicing factor in keratinocytes, fibroblasts, endothelial cells, and perivascular inflammatory cells. Circulating levels of VEGF165 b were significantly higher in patients with SSc than in control subjects. Microvascular endothelial cells (MVECs) isolated from SSc skin expressed and released higher levels of VEGF165 b than healthy MVECs. Transforming growth factor-β1 upregulated the expression of VEGF165 b and serine/arginine protein 55 in both SSc and healthy MVECs. In SSc MVECs, VEGF receptor-2 was overexpressed, but its phosphorylation was impaired. Recombinant VEGF165 b and SSc-MVEC–conditioned medium inhibited VEGF165 -mediated VEGF receptor-2 phosphorylation and capillary morphogenesis in healthy MVECs. The addition of anti-VEGF165 b blocking antibodies abrogated the antiangiogenic effect of SSc-MVEC–conditioned medium. Capillary morphogenesis was severely impaired in SSc MVECs and could be ameliorated by treatment with recombinant VEGF165 and anti-VEGF165 b blocking antibodies.Conclusions: In SSc, a switch from proangiogenic to antiangiogenic VEGF isoforms may have a crucial role in the insufficient angiogenic response to chronic ischemia.

circulation research

Overexpression of VEGF <sub>165</sub> b, an Inhibitory Splice Variant of Vascular Endothelial Growth Factor, Leads to Insufficient Angiogenesis in Patients With Systemic Sclerosis

Overexpression of VEGF 165 b, an Inhibitory Splice Variant of Vascular Endothelial Growth Factor, Leads to Insufficient Angiogenesis in Patients With Systemic Sclerosis

Overexpression of VEGF ₁₆₅ b, an Inhibitory Splice Variant of Vascular Endothelial Growth Factor, Leads to Insufficient Angiogenesis in Patients With Systemic Sclerosis