Background Smooth muscle cells (SMCs) are the main driver of neointima formation and restenosis following vascular injury. In animal models, endothelial progenitor cells (EPCs) accelerate endothelial regeneration and reduce neointima formation after arterial injury; however, EPC-capture stents do not reduce target vessel failure compared with conventional stents. Here we examined the influence of EPCs on features of SMCs pivotal for their impact on injury-induced neointima formation including proliferation, migration, and phenotype switch.

Methods and Results EPCs, their conditioned medium, and EPC-derived microparticles induced proliferation of SMCs while limiting their apoptosis. In transwell membrane experiments and scratch assays, EPCs stimulated migration of SMCs and accelerated their recovery from scratch-induced injury. Treatment of SMCs with an EPC-derived conditioned medium or microparticles triggered transformation of SMCs toward a synthetic phenotype. However, co-cultivation of EPCs and SMCs enabling direct cell–cell contacts preserved their original phenotype and protected from the transformative effect of SMC cholesterol loading. Adhesion of EPCs to SMCs was stimulated by SMC injury and reduced by blocking CXCR2 and CCR5. Interaction of EPCs with SMCs modulated their secretory products and synergistically increased the release of selected chemokines. Following carotid wire injury in athymic mice, injection of EPCs resulted not only in reduced neointima formation but also in altered cellular composition of the neointima with augmented accumulation of SMCs.

Conclusion EPCs stimulate proliferation and migration of SMCs and increase their neointimal accumulation following vascular injury. Furthermore, EPCs context-dependently modify the SMC phenotype with protection from the transformative effect of cholesterol when a direct cell–cell contact is established.

背景 平滑肌细胞 (SMC) 是血管损伤后新内膜形成和再狭窄的主要驱动因素。在动物模型中，内皮祖细胞 (EPC) 可加速内皮细胞再生并减少动脉损伤后的新内膜形成；然而，与传统支架相比，EPC 捕获支架并不能减少靶血管故障。在这里，我们检查了 EPC 对 SMC 特征的影响，这些特征对它们对损伤诱导的新内膜形成的影响至关重要，包括增殖、迁移和表型转换。

方法和结果 EPC、它们的条件培养基和EPC衍生的微粒诱导SMC增殖，同时限制它们的细胞凋亡。在 transwell 膜实验和划痕试验中，EPC 刺激了 SMC 的迁移并加速了它们从划痕引起的损伤中恢复。用 EPC 衍生的条件培养基或微粒处理 SMC 会引发 SMC 向合成表型的转化。然而，EPCs 和 SMCs 的共培养能够实现直接的细胞-细胞接触，保留了它们的原始表型，并保护了它们免受 SMC 胆固醇负荷的转化作用。SMC 损伤刺激 EPC 与 SMC 的粘附，并通过阻断 CXCR2 和 CCR5 减少。EPCs 与 SMCs 的相互作用调节了它们的分泌产物并协同增加了选定趋化因子的释放。

结论 EPCs 刺激 SMCs 的增殖和迁移，增加血管损伤后新生内膜的积累。此外，当建立直接的细胞 - 细胞接触时，EPCs 上下文依赖性地修改 SMC 表型，保护免受胆固醇的转化作用。