Nicotine Enlivenment of Blood Flow Recovery Following Endothelial Progenitor Cell Transplantation into Ischemic Hindlimb

Abstract

Nicotine has been demonstrated to stimulate postnatal angiogenesis, having an antiapoptotic effect on endothelial cells. Given the extent of this angiogenesis-promoting effect, we hypothesized that nicotine may also stimulate postnatal vasculogenesis on endothelial progenitor cells (EPCs). Our analyses reveal some intriguing results using an in vitro assay with 2 x 10(-6) M of nicotine (smoker's average nicotine concentration and the dose of nicotine replacement therapy). The proliferation and migration activities of human EPCs cultured from peripheral blood mononuclear cells of non-smoking healthy volunteers were not affected by nicotine. The effect of nicotine on EPC survival was significantly enhanced under serum starvation on the ratio of Hoechest 33342-stained pyknotic nuclear cells as well as Annexin-V-stained cells to total cells. Furthermore, the antiapoptotic effect of nicotine was blocked completely by nicotinic acetylcholine receptor (nAChR) antagonist hexamethonium. Next, we verified how nicotine acts in vivo. Nicotine (100 ng/ml) was administered orally for 7 days before and 4 weeks after injection of cultured EPCs (1 x 10(5) /mouse) into the tail veins of 8-week-old athymic nude mice with ischemic hindlimbs. Laser doppler imaging analysis indicated that blood perfusion in the ischemic hindlimb was significantly enhanced in EPCs plus nicotine, as compared with EPCs alone. These findings suggest nicotine improves blood flow following EPC transplantation in patients with ischemic diseases.

Long-term nicotine exposure induces dysfunction of mouse endothelial progenitor cells

“…EPC dysfunction is common in chronic smokers, but increasing evidence suggests that short-term nicotine exposure presents benefits to EPCs (12). In the present study, the long-term effects of nicotine on EPCs were investigated.…”

“…Wang et al (11) reported that low concentrations of nicotine increase the EPC count and their proliferative, migratory, adhesive and vasculogenic capacity. Furthermore, nicotine administration improved the blood flow in a rat ischemic hindlimb model by enhancing the function of transplanted EPCs (12). A hypothesized explanation of these effects was that nicotine reduced EPC senescence by activating telomerase through the PI3K/Akt pathway (13).…”

Current perspective of pathophysiological and interventional effects on endothelial progenitor cell biology: Focus on Pi3K/AKT/eNOS pathway

“…Furthermore, a direct antiapoptotic effect of nicotine, when added to EPC culture media, was demonstrated. In an ischemic hindlimb model, nicotine treatment of early outgrowth EPC transplanted mice improved blood flow recovery in comparison to transplantation of EPC alone [87].…”

Nicotinic Acetylcholine Receptor Signaling in Tumor Growth and Metastasis

“…Nicotine has been demonstrated to stimulate postnatal angiogenesis, having an antiapoptotic effect on endothelial cells. It was observed that nicotine stimulated postnatal vasculogenesis on endothelial progenitor cells (EPCs) [75]. The effect of nicotine on EPC survival was significantly enhanced under serum starvation.…”

“…The effect of nicotine on EPC survival was significantly enhanced under serum starvation. Furthermore, the antiapoptotic effect of nicotine was blocked completely by nicotinic acetylcholine receptor (nAChR) antagonist hexamethonium bromide [75]. …”