Abstract 15387: Bone Marrow-Derived Kruppel-Like Factor 10 (KLF10) Controls Re-Endothelialization in Response to Arterial Injury
Background: Emerging evidence demonstrates that endothelial progenitor cells (EPCs) may originate from the bone marrow and are capable of being recruited to sites of vascular injury and contribute to endothelial repair. However, the factors and signaling pathways that regulate vascular re-endothelialization remain poorly understood.
Methods and Results: We previously identified a TGF-b1-responsive Kruppel-like Factor, KLF10, as robustly expressed in EPCs derived from the bone marrow. KLF10-/- mice have marked defects in circulating EPCs (-23.6% vs. WT, P<0.004) and decreased rates of migration in transwell Boyden chambers (WT 692 vs. KO 298.6, P<0.001). To examine the role of KLF10 in vascular re-endothelialization, we used a model of wire-induced endothelial injury of the carotid artery using a 4 mm-wire passed 5 times in KLF10-/- or WT mice. The amount of re-endothelialization in the carotids was determined after Evans Blue systemic perfusion. 3 and 7 days after injury, WT mice displayed higher areas of re-endothelialization compared to KLF10-/- mice (day 3: WT 52.4% vs. KLF10-/- 30.6%, P=0.045; Day 7: WT 95.1% vs. KLF10-/- 75.1%, P=0.033). To examine the contribution of KLF10 from the bone marrow, we performed bone marrow transplantation (BMT) studies and examined re-endothelialization after 3 days in 4 groups (n=4-8 mice/group): WT BMT into WT recipient mice (WT->WT), KLF10-/- BMT into WT recipient mice (KLF10-/-->WT), WT BMT into KLF10 recipient mice (WT->KLF10-/-), and KLF10-/- BMT into KLF10-/- recipient mice (KLF10-/---> KLF10-/-). Three days after wire-induced endothelial injury of the carotid arteries, re-endothelialization areas were: WT->WT 54.36%. vs. KLF10-/-->WT 21.1%, P=0.042); WT->KLF10-/- 49.4% vs. KLF10-/-->KLF10-/- 19.5%, P=0.044). Examination of the carotid arteries and peripheral blood demonstrated marked reductions in lin-Sca-1+KDR+ EPCs (24-36%, P<0.04) in KLF10-/-->WT and KLF10-/-->KLF10-/- mice compared to WT->WT mice, an effect that was completely rescued in WT->KLF10-/- mice.
Conclusion: Collectively, these observations identify that bone marrow-derived KLF10 regulates EPC differentiation and function and may provide a therapeutic target to promote endothelial repair in response to arterial injury.
- © 2011 by American Heart Association, Inc.