Abstract
Endothelial progenitor cells (EPCs) play a vital role in endothelial repair following vascular injury by maintaining the integrity of endothelium. As EPCs home to endothelial injury sites, they may communicate with exposed vascular smooth muscle cells (VSMCs), which are subjected to cyclic stretch generated by blood flow. In this study, the synergistic effect of cyclic stretch and communication with neighboring VSMCs on EPC function during vascular repair was investigated. In vivo study revealed that EPCs adhered to the injury site and were contacted to VSMCs in the Sprague–Dawley (SD) rat carotid artery injury model. In vitro, EPCs were cocultured with VSMCs, which were exposed to cyclic stretch at a magnitude of 5% (which mimics physiological stretch) and a constant frequency of 1.25 Hz for 12 h. The results indicated that stretched VSMCs modulated EPC differentiation into mature endothelial cells (ECs) and promoted angiogenesis. Meanwhile, cyclic stretch upregulated the mRNA expression and secretion level of connective tissue growth factor (CTGF) in VSMCs. Recombinant CTGF (r-CTGF) treatment promoted endothelial differentiation of EPCs and angiogenesis, and increased their protein levels of FZD8 and β-catenin. CTGF knockdown in VSMCs inhibited cyclic stretch-induced EPC differentiation into ECs and attenuated EPC tube formation via modulation of the FZD8/β-catenin signaling pathway. FZD8 knockdown repressed endothelial differentiation of EPCs and their angiogenic activity. Wnt signaling inhibitor decreased the endothelial differentiation and angiogenetic ability of EPCs cocultured with stretched VSMCs. Consistently, an in vivo Matrigel plug assay demonstrated that r-CTGF-treated EPCs exhibited enhanced angiogenesis; similarly, stretched VSMCs also induced cocultured EPC differentiation toward ECs. In a rat vascular injury model, r-CTGF improved EPC reendothelialization capacity. The present results indicate that cyclic stretch induces VSMC-derived CTGF secretion, which, in turn, activates FZD8 and β-catenin to promote both differentiation of cocultured EPCs into the EC lineage and angiogenesis, suggesting that CTGF acts as a key intercellular mediator and a potential therapeutic target for vascular repair.
Highlights
Vascular injury leads to the initiation and progression of atherosclerotic vascular disease and may result in neointimal hyperplasia, in-stent restenosis, and acute stent thrombosis (Deanfield et al, 2007)
In the initial stage of intimal injury, Endothelial progenitor cells (EPCs) are mobilized to the injury site; we examined the adhesion of EPCs 1 h after intimal injury, which were identified by von Willebrand factor (vWF) (EC marker) and CD34 expression
In vivo experiment results suggested that carotid intimal injury caused EPCs homing and adhering to the injury site, which were connected to the exposed vascular smooth muscle cells (VSMCs), which are subjected to physiological stretch at the damaged intima
Summary
Vascular injury leads to the initiation and progression of atherosclerotic vascular disease and may result in neointimal hyperplasia, in-stent restenosis, and acute stent thrombosis (Deanfield et al, 2007). EPCs are mobilized and home to the injury sites and differentiate into ECs, which participate in angiogenesis, neovascularization, and tissue repair (Asahara et al, 1997; Deanfield et al, 2007; Zhang et al, 2014; Li et al, 2019). In this process, EPCs communicate with the exposed vascular smooth muscle cells (VSMCs), which compose the medial layer of the vessel wall. The impact of VSMCs on EPC function or the underlying signal mechanisms is little known
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