Abstract
Cells mobilized from the bone marrow can contribute to endothelial regeneration and repair. Nevertheless, cardiovascular diseases are associated with diminished numbers and function of these cells, attenuating their healing potential. Gene transfer of endothelial nitric oxide synthase (eNOS) can restore the activity of circulating cells. Furthermore, estrogen accelerates the reendothelialization capacity of early outgrowth cells (EOCs). We hypothesized that overexpressing eNOS alone or in combination with estrogen stimulation in EOCs would potentiate the beneficial effects of these cells in regulating smooth muscle cell (SMC) function. Native human EOCs did not have any effect on human coronary artery SMC (hCASMC) proliferation or migration. Transfecting EOCs with a human eNOS plasmid and/or stimulating with 17β-estradiol (E2) increased NO production 3-fold and enhanced EOC survival. Moreover, in co-culture studies, eNOS overexpressing or E2-stimulated EOCs reduced hCASMC migration (by 23% and 56% respectively), vs. control EOCs. These effects do not implicate ERK1/2 or focal adhesion kinases. Nevertheless, NOS-EOCs had no effect on hCASMC proliferation. These results suggest that overexpressing or activating eNOS in EOCs increases their survival and enhances their capacity to regulate SMC migration through paracrine effects. These data elucidate how eNOS overexpression or activation in EOCs can prevent vascular remodeling.
Highlights
Endothelial damage and dysfunction contribute to the development of atherosclerosis, coronary heart disease and restenosis after angioplasty
early outgrowth cells (EOCs) were seeded in cell culture well inserts, such that any effects on smooth muscle cell (SMC) would be through paracrine stimulation rather than direct contact
We did not observe any supplemental effect of combined treatments on human coronary artery SMC (hCASMC) migration or proliferation (Fig. 7). These results indicate that despite an increased Nitric oxide (NO) production in EOCs both transfected with endothelial nitric oxide synthase (eNOS) and treated with E2, there is no further effect on hCASMC function
Summary
Endothelial damage and dysfunction contribute to the development of atherosclerosis, coronary heart disease and restenosis after angioplasty. Loss of EC function promotes changes in vascular smooth muscle cell (SMC) proliferation, migration and extracellular matrix production[2]. This issue is a prominent feature of restenosis after angioplasty. Estrogen treatment causes EOCs to secrete more growth factors and facilitates their integration at sites of angiogenesis[11]. Both estrogen and statins have been shown to act through www.nature.com/scientificreports/. We observed that eNOS-overexpressing or estrogen-stimulated EOCs have an increased survival and inhibit migration of SMCs through paracrine effects
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