A critical role of CXCR2 PDZ-mediated interactions in endothelial progenitor cell homing and angiogenesis

Yuning Hou,Yanning Wu,Shukkur M Farooq,Xiaoqing Guan,Shuo Wang,Yanxia Liu,Jacob J Oblak,Joshua Holcomb,Yuanyuan Jiang,Robert M Strieter,Robert D Lasley,Ali S Arbab,Fei Sun,Chunying Li,Zhe Yang

doi:10.1016/j.scr.2014.12.001

Abstract

Bone marrow-derived endothelial progenitor cells (EPCs) contribute to neovessel formation in response to growth factors, cytokines, and chemokines. Chemokine receptor CXCR2 and its cognate ligands are reported to mediate EPC recruitment and angiogenesis. CXCR2 possesses a consensus PSD-95/DlgA/ZO-1 (PDZ) motif which has been reported to modulate cellular signaling and functions. Here we examined the potential role of the PDZ motif in CXCR2-mediated EPC motility and angiogenesis. We observed that exogenous CXCR2 C-tail significantly inhibited in vitro EPC migratory responses and angiogenic activities, as well as in vivo EPC angiogenesis. However, the CXCR2 C-tail that lacks the PDZ motif (ΔTTL) did not cause any significant changes of these functions in EPCs. In addition, using biochemical assays, we demonstrated that the PDZ scaffold protein NHERF1 specifically interacted with CXCR2 and its downstream effector, PLC-β3, in EPCs. This suggests that NHERF1 might cluster CXCR2 and its relevant signaling molecules into a macromolecular signaling complex modulating EPC cellular functions. Taken together, our data revealed a critical role of a PDZ-based CXCR2 macromolecular complex in EPC homing and angiogenesis, suggesting that targeting this complex might be a novel and effective strategy to treat angiogenesis-dependent diseases.

Highlights

Derived from bone marrow, endothelial progenitor cells (EPCs) contribute to the adult vascularization through secreting pro-angiogenic factors and incorporating into angiogenic sites to differentiate into mature endothelial cells [4, 18]
Based on our previous finding of PDZ based CXCR2 involved macromolecular complex in neutrophil and pancreatic cancer cells [50, 96], the biochemical study of my research has suggested a CXCR2-NHERF1-PLCβ3 complex in EPCs
I have found that the chemotaxis stimulus of EPCs activated RhoA in the EPCs and disrupting the CXCR2 PDZ-mediated protein-protein interactions attenuated the activation of RhoA as well as downstream signaling molecules including p38 MAPK, ERK1/2, and Akt

Summary

Introduction

Thanks to Asahara and coworkers’ isolation of endothelial progenitor cells (EPCs) from human peripheral blood, our understanding to the mechanism responsible for new blood vessel formation was extended [2]. Their discovery of EPCs has introduced the concept of vasculogenesis [2]. It is reported that EPCs are decreased in artery disease [9,10,11] but elevated in several types of cancer [12] These studies have highlighted the potential importance of EPCs in neovascularization or angiogenesis related diseases [13].

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Conclusion