Abstract
Hypoxia-associated pulmonary hypertension is characterized by pulmonary vascular remodeling. Pulmonary arterial endothelial cells dysfunction is considered as the initial event. As precursor of endothelial cells, endothelial colony-forming cells (ECFCs) play significant roles in maintenance of endothelium integrity and restoration of normal endothelial cell function. Accumulating data have indicated that hypoxia leads to a decrease in the number and function of ECFCs with defective capacity of endothelial regeneration. Previous studies have reported that the activation of ATP-sensitive potassium channels (K(ATP)) shows therapeutic effects in pulmonary hypertension. However, there have been few reports focusing on the impact of K(ATP) on ECFC function under hypoxic condition. Therefore, the aim of this study was to investigate whether the opening of K(ATP) could regulate hypoxia-induced ECFC dysfunction. Using ECFCs derived from adult peripheral blood, we observed that Iptakalim (Ipt), a novel K(ATP) opener (KCO), significantly promoted ECFC function including cellular viability, proliferation, migration, angiogenesis, and apoptosis compared with ECFCs exposed to hypoxia. Glibenclamide (Gli), a nonselective K(ATP) blocker, could eliminate the effects. The protective role of Ipt is attributed to an increased production of nitric oxide (NO), as well as an enhanced activation of angiogenic transduction pathways, containing Akt and endothelial nitric oxide synthase. Our observations demonstrated that K(ATP) activation could improve ECFC function in hypoxia via Akt/endothelial nitric oxide synthase pathways, which may constitute increase ECFC therapeutic potential for hypoxia-associated pulmonary hypertension treatment.