Estrogen Increases Bone Marrow–Derived Endothelial Progenitor Cell Production and Diminishes Neointima Formation

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Abstract
Background— Estrogens improve endothelial function and accelerate reendothelialization after vascular injury via largely unknown mechanisms. Bone marrow–derived endothelial progenitor cells (EPCs) are thought to positively influence endothelialization, vascular repair, and angiogenesis. Methods and Results— In mice subjected to sham operation, ovariectomy, or ovariectomy and estrogen replacement treatment, estrogen deficiency significantly decreased EPCs circulating in the peripheral blood and residing in the bone marrow, as well as EPCs that were in vitro expanded from spleen-derived mononuclear cells. These effects were completely prevented by estrogen replacement. Human women with increased estrogen plasma concentrations also displayed profoundly increased levels of circulating EPCs. Estrogens increase EPC numbers through a decreased apoptosis rate, which is mediated via a caspase-8–dependent pathway. Estrogen deficiency increased neointima formation after carotid artery injury in mice, but this effect was diminished by estrogen replacement therapy. In mice transplanted with green fluorescent protein–positive bone marrow, reendothelialization of injured vessel segments by bone marrow–derived cells was decreased during estrogen deficiency and increased in response to estrogen treatment. Conclusions— Estrogens increase numbers of EPCs by antiapoptotic effects leading to accelerated vascular repair and decreased neointima formation.