Access Type

Open Access Embargo

Date of Award

January 2016

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Biochemistry and Molecular Biology

First Advisor

Chunying Li

Abstract

Bone marrow-derived endothelial progenitor cells (EPCs) participate in postnatal vascularization 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 at its carboxyl terminus. The PDZ motif has been reported to regulate cellular signaling and functions. Here we investigated the potential role of the PDZ motif in CXCR2-mediated EPC motility and angiogenesis. We have found that introducing exogenous CXCR2 C-terminus significantly attenuated in vitro EPC migration and angiogenic activities in response to CXCR2 ligands, as well as in vivo EPC angiogenesis. Meanwhile, the activation of RhoA, p38, ERK1/2, and Akt has also been inhibited due to the exogenous CXCR2 C-terminus. On the other hand, delivering CXCR2 C-terminus without PDZ motif into EPCs did not significantly affect the functions of EPCs. Moreover, biochemistry study suggested that NHERF1, a PDZ domain containing scaffolding protein, preferred to interact with CXCR2 and its downstream effector, PLC-β3 in EPCs. Taken together, the data has demonstrated the role of CXCR2 PDZ motif-mediated macromolecular complex in EPC homing and angiogenesis and also indicated potentially involved signaling pathways. The findings suggested that targeting CXCR2 PDZ motif-mediated interactions in EPCs may be a novel therapeutic approach in EPC dependent angiogenesis related diseases.

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