Hypoxia-induced interstitial transformation of microvascular endothelial cells by mediating HIF-1α/VEGF signaling in systemic sclerosis

Objective The aim of this research was to systematically investigate the effects of endothelial mesenchymal transition (EndMT) induced by hypoxia on the skin microvascular remodeling of systemic sclerosis (SSc) and the underlying mechanism. Methods Skin tissues from SSc patients and controls were collected for isobaric tags for the relative and absolute quantification (iTRAQ)-based proteomics and immunohistochemical test. Human microvascular endothelial cell line-1 (HMEC-1) cultured in hypoxic or normal conditions was treated by tamoxifen or bevacizumab. Results The iTRAQ-based proteomics indicated a significantly upregulated hypoxia-inducible factor-1 (HIF-1) signal in SSc samples. The immunohistochemical results demonstrated the significant downregulation of CD31, the positive staining of alpha-smooth muscle actin (alpha-SMA), HIF-1 alpha, and vascular endothelial growth factor (VEGF-a) in SSc skin tissues, compared with control samples. Consistent with these observations, HMEC-1 cells cultured under hypoxic conditions exhibited a significant decrease in CD31 and VE-cadherin expression, alongside a marked increase in the expression of alpha-SMA and fibronectin, as well as a distinct upregulation of HIF-1 alpha and VEGF-a, when compared with those under normal conditions. It is noteworthy that the inhibition of HIF-1 alpha by tamoxifen effectively downregulated the hypoxic induction of VEGF-a and alpha-SMA while rescuing the hypoxic suppression of CD31. In addition, the VEGF-a inhibitor bevacizumab treatment had the same effect on the hypoxic expression of alpha-SMA and CD31, as a tamoxifen intervention, but did not reduce HIF-1 alpha. Conclusion These results suggest that the HIF-1 alpha/VEGF signaling pathway can have a critical role in mediating the effect of hypoxia-induced EndMT on the skin microvascular remodeling of SSc.

Automated summary

This research systematically investigates the effects of hypoxia-induced endothelial mesenchymal transition (EndMT) on skin microvascular remodeling in systemic sclerosis (SSc) and its underlying mechanism. The results suggest that the HIF-1α/VEGF signaling pathway plays a critical role in mediating the effect of hypoxia-induced EndMT on skin microvascular remodeling in SSc.