Abstract
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.
Keywords
restenosis - endothelial progenitor cells - smooth muscle cells - vascular injury
- neointima
