The ratios of Ang1/Ang2 and Ang1/VEGF were significantly lower in SSc patients (8.346 ± 4.523 and 95.17 ± 75.0, respectively) than in healthy subjects (17.612 ± 6.731 p < 0.000001 and 183.11 ± 137.73; p = 0.004].
The genesis of tissue edema is tightly linked to pathological changes in the endothelium: various reports demonstrated the effect of transforming growth factor β, vascular endothelial growth factor and hypoxia-reperfusion damage with reactive oxygen species generation in altering vascular permeability and extravasation, in particular in SSc.
We also examined the mechanisms underlying the effects of α2AP on vascular alteration in SSc and found that α2AP attenuated vascular endothelial growth factor-induced tube formation, cell proliferation, and endothelial junction-associated protein production through the adipose triglyceride lipase/tyrosine phosphatase SHP2 axis in ECs.
Patients with SSc also displayed higher serum levels of VEGF, endothelin-1 and s-Fractalkine. s-Fractalkine levels positively correlated with CD34<sup>+</sup>CD45<sup>-</sup> EPC numbers.
In systemic sclerosis (SSc), vascular involvement is characterised by vascular endothelial growth factor (VEGF)-A/VEGF receptor (VEGFR) system disturbances.
After sorting, we showed: i. an increased production of vascular endothelial growth factor A (VEGF-A) in SSc-MSCs when co-cultured with SSc-ECs; ii. an increased level of transforming growth factor beta (TGF-β) and platelet growth factor BB (PDGF-BB) in SSc-ECs when co-cultured with both HC- and SSc-MSCs; iii. an increase of TGF-β, PDGF-R, alpha smooth muscle actin (α-SMA) and collagen 1 (Col1) in both HC- and SSc-MSCs when co-cultured with SSc-ECs.
We found that bp -532 to -521 on the VEGF promoter is a putative binding site for Smads, and that the binding activity of Smad3 to VEGF promoter was constitutively increased in SSc fibroblasts as well as in normal fibroblasts treated with exogenous TGF-β1.
SA 96, and particularly its metabolite SA 981, increased the levels of vascular endothelial growth factor (VEGF) mRNA and protein dose-dependently in dermal fibroblasts from patients with SSc and healthy control subjects without influencing cell viability.
Considering our observation that PDGF and IL-1beta costimulated VEGF expression, we propose that chronic and uncontrolled VEGF upregulation that is mediated by an orchestrated expression of cytokines rather than VEGF downregulation is the cause of the disturbed vessel morphology in the skin of SSc patients.