Abstract 5591: KLF2 Restores Neovascularization Capacity of Aged Proangiogenic Cells
Coronary artery disease (CAD) patients have less circulating endothelial progenitor cells (EPCs), which exhibit impaired neovascularization properties. Inverse correlations were also found between EPC function and risk factors like age. Krüppel-like factor 2 (KLF2) is expressed by mature endothelial cells (ECs), is induced by both shear stress and statins and provokes endothelial functional differentiation. Here, we describe that early EPCs, also known as proangiogenic cells (PACs), express KLF2 at a comparable level to mature ECs and that senescence decreases KLF2 levels. To study the effects of aging on KLF2 levels, we compared progenitor cells of 4 weeks and 16 –18 months old C57BL/6 mice. In addition to the 2.5-fold reduction of circulating Sca1+/c-Kit+/Lin- progenitor cells and the 40% reduction of Sca1+/Flk1+ endothelial committed progenitor cells, the spleen-derived PACs isolated from aged mice showed a 60% lower level of KLF2 when compared to PACs isolated from young mice. Moreover, PACs isolated from peripheral blood of aged CAD patients were shown to contain 3-fold less KLF2 than PACs isolated from healthy young controls. Lentiviral overexpression of KLF2 increased human PAC numbers by 60% during in vitro culture. Endothelial lineage-specific KLF2 overexpression in aged bone marrow-derived mononuclear cells strongly augments neovascularization in vivo in a murine hind-limb ischemia model. These results imply that KLF2 is an attractive novel target to rejuvenate PACs before autologous administration to CAD patients.