Krüppel-like factor 2 improves neovascularization capacity of aged proangiogenic cells

Reinier A. Boon, Carmen Urbich, Ariane Fischer, Ruud D. Fontijn, Florian H. Seeger, Masamichi Koyanagi, Anton J.G. Horrevoets, Stefanie Dimmeler

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34 Citations (Scopus)

Abstract

AimsCoronary artery disease (CAD) patients have less circulating proangiogenic cells (PACs), formerly known as endothelial progenitor cells, which exhibit impaired neovascularization properties. Inverse correlations were also found between PAC function and risk factors like age. Krppel-like factor 2 (KLF2) is expressed by mature endothelial cells (ECs), is induced by both shear stress and statins, and provokes endothelial functional differentiation. The aim of this study is to identify whether KLF2 can reverse negative effects of ageing on PAC function.Methods and resultsWe describe that progenitor cells in the bone marrow and PACs also express KLF2 at a comparable level to mature ECs and that senescence decreases KLF2 levels. To study the effects of ageing on KLF2 levels, we compared progenitor cells of 4 weeks and 16- to 18-month-old C57BL/6 mice. In addition to the three-fold reduction of circulating Sca1 +/c-Kit+/Lin- progenitor cells and the 15% reduction of Sca1+/Flk1+ endothelial-committed progenitor cells, the spleen-derived PACs and bone marrow-derived progenitor cells isolated from aged mice showed a lower level of KLF2 when compared with young mice. Lentiviral overexpression of KLF2 increased human PAC numbers and endothelial nitric oxide synthase expression 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 ischaemia model.ConclusionThese results imply that KLF2 is an attractive novel target to rejuvenate PACs before autologous administration to CAD patients.

Original languageEnglish
Pages (from-to)371-377
Number of pages7
JournalEuropean heart journal
Volume32
Issue number3
DOIs
Publication statusPublished - Feb 1 2011

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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    Boon, R. A., Urbich, C., Fischer, A., Fontijn, R. D., Seeger, F. H., Koyanagi, M., Horrevoets, A. J. G., & Dimmeler, S. (2011). Krüppel-like factor 2 improves neovascularization capacity of aged proangiogenic cells. European heart journal, 32(3), 371-377. https://doi.org/10.1093/eurheartj/ehq137