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

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

Estrogen-Mediated, Endothelial Nitric Oxide Synthase–Dependent Mobilization of Bone Marrow–Derived Endothelial Progenitor Cells Contributes to Reendothelialization After Arterial Injury

“…Moreover, these data disclose that estradiol has similar direct effects on EPCs, as have been documented in mature ECs, 2,29 inducing proliferation and migration and inhibiting apoptosis. These findings are consistent with those recently reported by Strehlow et al 27 and also add the important finding of an eNOS-dependent mechanism for the effects of estradiol on EPCs and endothelial recovery. Most notably, the present findings suggest that enhanced EPC mobilization and recruitment to sites of arterial injury may be the central feature of the beneficial effect of estradiol.…”

“…Quantification demonstrated that estradiol treatment significantly accelerated reendothelialization compared with the placebo treatment, as has been shown previously in the rat and mouse ( Figure 1B). 8,26,27 The inner surface of the carotid artery in each group was completely reendothelialized 14 days after the injury. Also consistent with prior studies, estradiol significantly inhibited the injury-induced increase in medial area ( Figure 1, C and D).…”

Angiotensin II promotes NO production, inhibits apoptosis and enhances adhesion potential of bone marrow-derived endothelial progenitor cells

“…Several cardiovascular risk factors have been shown to be associated with dysfunction and decreased numbers of EPCs, such as hypercholesterolemia [28], diabetes [29] and Creactive protein [27]. Conversely, exercise [30], statins [28] and estrogen [31] positively regulate EPCs. Additionally, in our study, AngII was also shown to be such a positive factor.…”

Alcohol Consumption Negates Estrogen-mediated Myocardial Repair in Ovariectomized Mice by Inhibiting Endothelial Progenitor Cell Mobilization and Function

“…Together, these studies provide evidence of direct actions of estradiol on the bone marrow and the regulation of bone marrow-derived precursor cells. Apart from the local induction of endothelial growth factors, the underlying proposed mechanisms of E2 also include the ability of E2 to mobilize EPCs, which can incorporate into denuded carotid arteries, thereby participating in the regeneration of the neo-endothelium (3,4). We and others (3,14,16) have also shown that E2-mediated enhancement in the recovery from AMI involves ischemic cardiac neovascularization, reduction in fibrosis, and enhanced expression of angiogenic growth factors in OVX mice receiving estradiol that is, at least in part, due to mechanisms involving eNOS and/or MMP9-dependent EPC mobilization, homing, and inhibition of apoptosis.…”