Abstract 3748: Prostacyclin Relieves Peripheral Ischemia through Enhancement of Critical Functions of Endothelial Progenitor Cells
[Background]: Prostacyclin (PGI2) plays an important role for regulation of peripheral circulation mainly through its potent vasodilative effect, and its analogues have been clinically introduced for the treatment of peripheral ischemia, particularly peripheral artery disease. We have reported that endothelial progenitor cells (EPC) express PGI2 specific receptor IP, and a deletion of IP in bone marrow (BM) modifies the functions of EPC in vivo and in vitro.
[Purpose]: To investigate whether PGI2 affects the pathogenesis of peripheral ischemia through EPC functions, we used a mouse model of hindlimb-ischemia (HLI) in which IP was deleted in BM.
[Methods and Results]: EPC (lineage-/cKit+/Flk1+ cells) were isolated from BM of wild and IP-deficient (IP−/−) mice. EPC (IP−/−) showed apparent attenuation of properties of adhesion to extracellular matrix and cellular migrations (reduction ratio of EPC (IP−/−), −52.1±8.0% (p<0.01) and −65.6±10.1% (p<0.01) respectively compared to that of EPC (wild)). Production of angiogenic cytokines, such as VEGF in EPC was also significantly decreased by 0.45 fold in EPC (IP−/−). BM cells of wild and IP−/− mice were transplanted to wild mice (wild/BM(wild) and wild/BM(IP−/−)), and peripheral circulation flow was estimated by laser Doppler image (LDI). As expected, recovery of perfusion flow in HLI of IP−/− mice was apparently reduced compared to wild mice (LDI Right/Left ratio, 0.29±0.02 versus 0.45±0.03, p<0.05). However, wild/BM(IP−/−), in which vascular IP was expressed but functional EPC was reduced by deletion of IP in BM, also demonstrated significant reduction of perfusion flow compared to that of wild/BM(wild) (LDI Right/Left ratio, 0.29±0.08 versus 0.51±0.07, p<0.05).
[Conclusions]: PGI2 /IP signal in BM may play an important role for protection system against peripheral ischemia through the enhancement of EPC functions. Accordingly EPC function could be new target of IP-stimulating drugs for therapeutic strategy of peripheral artery diseases.