Abstract 1310: Deletion Of Prostacyclin-receptor In Bone Marrow Attenuates Differentiation Of Endothelial Progenitor Cells, And Enhances Vascular Intimal Hyperplasia
Bone marrow (BM)-derived endothelial progenitor cells (EPC) contribute to re-endothelialization after endothelial cell injury, suppressing vascular remodeling. Prostacyclin (PGI2) has a potent anti-atherogenic function in vasculature. However, the role of PGI2 in differentiation of EPC is unclear. To investigate whether PGI2 affect the function of EPC under vascular remodeling, we used vascular injured mouse in which BM was lacking PGI2-specific receptor IP (IP-KO). Femoral arteries in sex-mismatched BM-transplanted (BMT) mice were injured by guide-wire. BM-cells of wild-type mice (Wt) or IP-KO were transplanted into Wt (Wt/BMT(wt) or Wt/BMT(IP-KO)). Neointimal thichness was pathologically evaluated and BM-derived endothelial cells (EC) in vascular wall were identified using CD31-immunostaining and in situ hybridization with Y-chromosome gene. At 4 weeks after vascular injury, neointima formation was terminated, and BM-derived EC were abundantly detected in luminal surface of injured arteries. Neointimal thickness in Wt/BMT(IP-KO) was significantly enhanced by 75% compared to that in Wt/BMT(wt) (n=14, p<0.01). EPC was determined by culture assay, according to fibronectin-adhensive, acetyl-LDL absorptive and lectin-binding properties. The number of EPC in BM and circulating blood of Wt/BMT(wt) was increased in response to injury. However, the value in Wt/BMT(IP-KO) was significantly reduced in basal condition and not respondent to vascular injury (n=6, p<0.01). EPC was isolated from Wt or IP-KO (EPC/wt or EPC/IP-KO) using magnet sorting system and cultured in VEGF-containing medium, and the differentiated EC were determined by vWF-immunostaining. The proliferation and differentiation of EPC were significantly reduced in EPC/IP-KO (n=6, p<0.01). EPC/wt, EPC/IP-KO or its vehicle saline were injected into vascular-injured Wt/BMT(IP-KO). The enhanced neointimal thickness in Wt/BMT(IP-KO) was significantly attenuated by EPC/wt, but not by EPC/IP-KO or saline (n=10, p<0.01). In conclusion, the neointimal hyperplasia might be negatively regulated by PGI2 through the differentiation of EPC. PGI2/IP system may play an important role in mediating functional EPC in BM, affecting pathogenesis of vascular remodeling.