Engagement of the CXCL12-CXCR4 Axis in the Interaction of Endothelial Progenitor Cell and Smooth Muscle Cell to Promote Phenotype Control and Guard Vascular Homeostasis.

Sebastian F Mause,Felix Vogt,Elisabeth Ritzel,Elisa A Liehn,Annika Deck

doi:10.3390/ijms23020867

Abstract

Endothelial progenitor cells (EPCs) are involved in vascular repair and modulate properties of smooth muscle cells (SMCs) relevant for their contribution to neointima formation following injury. Considering the relevant role of the CXCL12–CXCR4 axis in vascular homeostasis and the potential of EPCs and SMCs to release CXCL12 and express CXCR4, we analyzed the engagement of the CXCL12–CXCR4 axis in various modes of EPC–SMC interaction relevant for injury- and lipid-induced atherosclerosis. We now demonstrate that the expression and release of CXCL12 is synergistically increased in a CXCR4-dependent mechanism following EPC–SMC interaction during co-cultivation or in response to recombinant CXCL12, thus establishing an amplifying feedback loop Additionally, mechanical injury of SMCs induces increased release of CXCL12, resulting in enhanced CXCR4-dependent recruitment of EPCs to SMCs. The CXCL12–CXCR4 axis is crucially engaged in the EPC-triggered augmentation of SMC migration and the attenuation of SMC apoptosis but not in the EPC-mediated increase in SMC proliferation. Compared to EPCs alone, the alliance of EPC–SMC is superior in promoting the CXCR4-dependent proliferation and migration of endothelial cells. When direct cell–cell contact is established, EPCs protect the contractile phenotype of SMCs via CXCL12–CXCR4 and reverse cholesterol-induced transdifferentiation toward a synthetic, macrophage-like phenotype. In conclusion we show that the interaction of EPCs and SMCs unleashes a CXCL12–CXCR4-based autoregulatory feedback loop promoting regenerative processes and mediating SMC phenotype control to potentially guard vascular homeostasis.

Highlights

The multifaceted process of atherosclerotic intimal expansion and remodeling after vascular injury with subsequent progressive restenosis and target lesion failure constitutes a major limitation of therapeutic revascularization and are a relevant cause of morbidity and mortality worldwide [1,2]
Given the relevance of CXCL12 in the recruitment of progenitor cells, vascular repair and postinjury remodeling as well as primary and secondary atherosclerosis [8], we investigated the pattern of CXCL12 expression and release by endothelial progenitor cells (EPCs) and smooth muscles cells (SMCs) in monoculture and following co-cultivation allowing EPC–SMC interaction
Our data reveal that CXCL12–CXCR4 signaling is operative in the communication of EPCs and SMCs and hereby triggers an autoregulatory feedback loop for the increased release of CXCL12, mediates the augmentation of the migratory capacity of SMCs as well as protects and favors a contractile over a synthetic phenotype of SMCs

Summary

Introduction

The multifaceted process of atherosclerotic intimal expansion and remodeling after vascular injury with subsequent progressive restenosis and target lesion failure constitutes a major limitation of therapeutic revascularization and are a relevant cause of morbidity and mortality worldwide [1,2]. Given their distinctive plasticity allowing phenotypic transformation with stimulated synthesis of extracellular matrix and their capacity to proliferate and migrate, vascular smooth muscles cells (SMCs) are attributed a dominant and ambivalent role in atherosclerotic lesion development and neointima formation [3,4,5,6]. SMC accumulation in murine lesions was reduced in a hyperlipidemia-model with SMC-specific CXCR4 deletion and in an injury-model with endothelial-specific CXCR4 deletion [9,14]

Methods

Results

Conclusion