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Fig. 1 | Arthritis Research & Therapy

Fig. 1

From: The crowded crossroad to angiogenesis in systemic sclerosis: where is the key to the problem?

Fig. 1

Schematic illustration of the mechanisms impairing VEGF-A/VEGFR-2 angiogenic signal in SSc. Angiogenesis tightly depends on the balance of proangiogenic VEGF165 and antiangiogenic VEGF165b isoforms. In angiogenic conditions, VEGF165 predominates, whereas in SSc the balance shifts to favor the expression of the VEGF165b splice variant in different cell types, such as ECs, platelets, fibroblasts, and mononuclear inflammatory cells. In ECs, binding of VEGF165 to both VEGFR-2 and NRP1 coreceptor activates VEGFR-2 phosphorylation and multiple downstream signaling pathways that are necessary for angiogenesis. Moreover, uPAR interacts with VEGFR-2 and recruits LRP-1 to VEGFR-2, which induces internalization of VEGF165-bound VEGFR-2, a key step in the proangiogenic signal. In SSc, both a switch from proangiogenic VEGF165 to antiangiogenic VEGF165b, which is unable to bind NRP1, and concomitant NRP1 downregulation due to Fli1 transcription factor deficiency result in an insufficient tyrosine phosphorylation/activation of VEGFR-2 and incomplete or transient downstream signaling along with a differential intracellular trafficking of VEGFR-2 toward the degradative pathway, ultimately leading to impaired angiogenesis. In SSc ECs, MMP-12-mediated cleavage/inactivation of uPAR may further impair the VEGF-A/VEGFR-2 system. EC endothelial cell, Fli1 Friend leukemia integration 1, LRP-1 low-density lipoprotein receptor-related protein 1, MMP-12 matrix metalloproteinase-12, NRP1 neuropilin-1, SSC systemic sclerosis, uPAR urokinase-type plasminogen activator receptor, VEGF vascular endothelial growth factor, VEGFR vascular endothelial growth factor receptor

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