Ex vivo pretreatment of bone marrow mononuclear cells with endothelial NO synthase enhancer AVE9488 enhances their functional activity for cell therapy

Ken Ichiro Sasaki, Christopher Heeschen, Alexandra Aicher, Thomas Ziebart, Joerg Honold, Carmen Urbich, Lothar Rossig, Ulrike Koehl, Masamichi Koyanagi, Annisuddin Mohamed, Ralf P. Brandes, Hans Martin, Andreas M. Zeiher, Stefanie Dimmeler

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Abstract

Bone marrow mononuclear cells (BMC) from patients with ischemic cardiomyopathy (ICMP) show a reduced neovascularization capacity in vivo. NO plays an important role in neovascularization, and NO bioavailability is typically reduced in patients with ICMP. We investigated whether the impaired neovascularization capacity of ICMP patient-derived progenitor cells can be restored by pretreatment with the novel endothelial NO synthase (eNOS) transcription enhancer AVE9488 (AVE). Ex vivo pretreatment of BMC from patients with ICMP with AVE significantly increased eNOS mRNA expression by 2.1-fold (P < 0.05) and eNOS activity as assessed by ESR by >3-fold (P < 0.05). The increased eNOS expression was associated with an enhanced migratory capacity in vitro (P < 0.01) and improved neovascularization capacity of the infused BMC in an ischemic hind limb model in vivo (P < 0.001). The improvement in ischemic limb perfusion after infusion of AVE-pretreated BMC resulted in an increase in swimming time (P < 0.05). The enhancement of limb perfusion by AVE-treated BMC was abrogated by ex vivo pretreatment with the eNOS inhibitor NG-nitro-L-arginine methyl ester. Consistently, AVE showed no effect on the impaired migratory capacity of BMC derived from eNOS-deficient mice, documenting the specific involvement of NO. The reduced neovascularization capacity of BMC from patients with ICMP may limit their therapeutic potential in cell therapy studies. Here, we show that pharmacological enhancement of eNOS expression with AVE at least partially reverses the impaired functional activity of BMC from ICMP patients, highlighting the critical role of NO for progenitor cell function.

Original languageEnglish
Pages (from-to)14537-14541
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number39
DOIs
Publication statusPublished - Sep 26 2006

All Science Journal Classification (ASJC) codes

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    Sasaki, K. I., Heeschen, C., Aicher, A., Ziebart, T., Honold, J., Urbich, C., Rossig, L., Koehl, U., Koyanagi, M., Mohamed, A., Brandes, R. P., Martin, H., Zeiher, A. M., & Dimmeler, S. (2006). Ex vivo pretreatment of bone marrow mononuclear cells with endothelial NO synthase enhancer AVE9488 enhances their functional activity for cell therapy. Proceedings of the National Academy of Sciences of the United States of America, 103(39), 14537-14541. https://doi.org/10.1073/pnas.0604144103