CXCL12 enhances angiogenesis through CXCR7 activation in human umbilical vein endothelial cells

Min Zhang,Jialin C Zheng,Li Jiang,Dongsheng Xu,Yanyan Zhang,Lisha Qiu

doi:10.1038/s41598-017-08840-y

Abstract

Angiogenesis is the process by which new vessels form from existing vascular networks. Human umbilical vein endothelial cells (HUVECs) may contribute to the study of vascular repair and angiogenesis. The chemokine CXCL12 regulates multiple cell functions, including angiogenesis, mainly through its receptor CXCR4. In contrast to CXCL12/CXCR4, few studies have described roles for CXCR7 in vascular biology, and the downstream mechanism of CXCR7 in angiogenesis remains unclear. The results of the present study showed that CXCL12 dose-dependently enhanced angiogenesis in chorioallantoic membranes (CAMs) and HUVECs. The specific activation of CXCR7 with TC14012 (a CXCR7 agonist) resulted in the significant induction of tube formation in HUVECs and in vivo. Further evidence suggested that CXCL12 induced directional polarization and migration in the HUVECs, which is necessary for tube formation. Moreover, CXCR7 translocalization was observed during the polarization of HUVECs in stripe assays. Finally, treatment with TC14012 also significantly increased PI3K/Akt phosphorylation, and tube formation was blocked by treating HUVECs with an Akt inhibitor. Overall, this study indicated that CXCL12-stimulated CXCR7 acts as a functional receptor to activate Akt for angiogenesis in HUVECs and that CXCR7 may be a potential target molecule for endothelial regeneration and repair after vascular injury.

Highlights

Many reports have revealed that angiogenesis is a compensatory and protective response to ischemic diseases
To test whether CXCL12 induced angiogenesis in Human umbilical vein endothelial cells (HUVECs), we exposed the HUVECs to various doses of CXCL12 (0–100 ng/mL), and they showed dose-dependent enhancement of tube formation (Fig. 1A), proliferation (Fig. 1B) and migration (Fig. 1C) of the cells
These results revealed that CXCL12 induced angiogenesis in HUVECs in vitro

Summary

Introduction

Many reports have revealed that angiogenesis is a compensatory and protective response to ischemic diseases. Endothelial cells (ECs) express very low levels of CXCR7 under normal physiological conditions in vivo and normal culture conditions in vitro, CXCR7 expression is induced in activated EC. This has suggested that CXCR7 plays a role in EC during physiological stress. CXCR7 has been shown to play a key role in tumor endothelial cell (TEC) angiogenesis, and its inhibition. Considering the fact that aberrant Akt signaling leads to impaired angiogenesis and vascular remodeling[34], an important issue that requires further study is whether CXCR7 can activate Akt-mediated phosphorylation pathway, since it plays a role in angiogenesis. The present study aims to clarify the role of CXCR7 and the regulation of the PI3K/Akt pathway in neovascularization

Methods

Results

Conclusion