Open AccessEx vivo pretreatment of bone marrow mononuclear cells with endothelial NO synthase enhancer AVE9488 enhances their functional activity for cell therapy
Author(s) -
Ken Sasaki,
Christopher Heeschen,
Alexandra Aicher,
Thomas Ziebart,
Joerg Honold,
Carmen Urbich,
Lothar Rössig,
Ulrike Koehl,
Masamichi Koyanagi,
Annisuddin Mohamed,
Ralf P. Brandes,
Hans Martin,
Andreas M. Zeiher,
Stefanie Dimmeler
Publication year - 2006
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0604144103
Subject(s) - enos , arteriogenesis , neovascularization , medicine , ex vivo , in vivo , progenitor cell , angiogenesis , bone marrow , endothelial progenitor cell , endocrinology , nitric oxide synthase , pharmacology , stem cell , biology , nitric oxide , microbiology and biotechnology
Bone marrow mononuclear cells (BMC) from patients with ischemic cardiomyopathy (ICMP) show a reduced neovascularization capacityin 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 3-fold (P < 0.05). The increased eNOS expression was associated with an enhanced migratory capacityin vitro (P < 0.01) and improved neovascularization capacity of the infused BMC in an ischemic hind limb modelin 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 byex 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.