Enhanced endothelial progenitor cell mobilization and function through direct manipulation of hypoxia inducible factor-1α.

Abstract

Endothelial progenitor cells (EPCs) play a significant role in physiological and pathological hypoxia resistance and neovascularization processes. The ability to mobilize EPCs from bone marrow usually indicates a prognostic endpoint of several vascular diseases. Thus, it is of great value to study possible approaches for activating functional EPCs. The mobilization/homing of EPCs from bone marrow is signalled by stromal-derived factor-1 (SDF-1), which is regulated by the hypoxia-inducible factor-1α (HIF-1α). This study investigated the effects of directly manipulating HIF-1α on human EPCs in vitro. EPCs were isolated from human umbilical cord blood. Lentiviral vectors carrying HIF-1α and shRNA targeting HIF-1α were constructed for gene modification of the EPCs. Results demonstrated that after overexpression of HIF-1α by lentiviral transfection, the proliferative capacity of EPCs was elevated while the apoptosis was inhibited and vice versa. On the other hand, the expression of angiogenic-related cytokines including SDF-1 was upregulated on both gene and protein levels when EPCs were transfected with HIF-1α. These results indicate that direct HIF-1α manipulation over human EPCs is an effective method to promote EPC function and mobilization, thus suggest that drugs or reagents that elevate HIF-1α expression are capable of treating ischemic diseases.