Objective-Endothelial progenitor cells (EPCs) play an important role in the self-healing of a vascular injury by participating in the reendothelialization that limits vascular remodeling. We evaluated whether prostaglandin I 2 plays a role in the regulation of the function of EPCs to limit vascular remodeling. Ϫ cKit ϩ Flk-1 ϩ cells) were isolated from the bone marrow (BM) of wild-type (WT) mice or mice lacking the prostaglandin I 2 receptor IP (IP Ϫ/Ϫ mice). Reverse transcription-polymerase chain reaction analysis showed that EPCs among BM cells specifically express IP. The cellular properties of EPCs, adhesion, migration, and proliferation on fibronectin were significantly attenuated in IP-deficient EPCs compared with WT EPCs. In contrast, IP agonists facilitated these functions in WT EPCs, but not in IP-deficient EPCs. The specific deletion of IP in BM cells, which was performed by transplanting BM cells of IP Ϫ/Ϫ mice to WT mice, accelerated wire injury-mediated neointimal hyperplasia in the femoral artery. Notably, transfused WT EPCs, but not IP-deficient EPCs, were recruited to the injured vessels, participated in reendothelialization, and efficiently rescued the accelerated vascular remodeling. Key Words: vascular remodeling Ⅲ prostaglandin I 2 Ⅲ endothelial progenitor cells Ⅲ fibronectin Ⅲ adhesion V ascular remodeling characterized by neointimal hyperplasia frequently accompanies angioplasty and atherosclerosis. 1 The development of vascular remodeling is limited by a process of reendothelialization, 2 which is accomplished by covering the neointimal surface with a functional endothelial monolayer. Recently, endothelial progenitor cells (EPCs) have been established as the cells participating in reendothelialization. 3,4 EPCs, which originate in bone marrow (BM), are mobilized into peripheral circulation in response to vascular injury. 5,6 After mobilization, they are recruited to the injured vessels, differentiate into mature endothelial cells, and contribute to reendothelialization to a variable extent depending on the nature of the vascular injury. 7-9 Accordingly, the infusion of exogenous EPCs 8,9 or EPC-mobilizing factors, 7,10 which increases circulatory EPCs, facilitated reendothelialization of the injured vessels and thereby suppressed neointimal formation. Methods and Results-EPCs (Lin Conclusion-These See accompanying article on page 457Prostaglandin (PG) I 2 (prostacyclin), a potent antiatherogenic lipid mediator, is the major prostanoid in the cardiovascular system and is produced mainly by vascular endothelial cells. PGI 2 exerts a variety of actions via binding to the specific receptor IP and, thus, induces vascular relaxation, inhibits proliferation of vascular smooth muscle cells, and potently inhibits platelet activation. 11 Accordingly, mice lacking the IP (IP Ϫ/Ϫ mice) have shown the phenotypes characterized by enhanced vascular remodeling with augmented neointimal hyperplasia after a vascular injury 12 and by facilitated atherosclerosis when having a concomitant loss of apoprote...

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Ischemic preconditioning (IPC) describes a phenomenon wherein brief ischemia of the heart induces a potent cardioprotective mechanism against succeeding ischemic insult. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in prostanoid biosynthesis, is upregulated in the ischemic heart and contributes to IPC. Prostaglandin E2 (PGE2) protects the heart from ischemia–reperfusion (I/R) injury via its receptor subtype EP4. We sought to clarify the role of the PGE2/EP4 system in the late phase of IPC. Mice were subjected to four IPC treatment cycles, consisting of 5 min of occlusion of the left anterior descending coronary artery (LAD). We found that COX-2 mRNA was significantly upregulated in wild-type hearts at 6 h after IPC treatment. Cardiac PGE2 levels at 24 h after IPC treatment were significantly increased in both wild-type mice and mice lacking EP4 (EP4–/–). At 24 h after IPC treatment, I/R injury was induced by 30 min of LAD occlusion followed by 2 h of reperfusion and the cardiac infarct size was determined. The infarct size was significantly reduced by IPC treatment in wild-type mice; a reduction was not observed in EP4–/– mice. AE1-329, an EP4 agonist, significantly reduced infarct size and significantly ameliorated deterioration of cardiac function in wild-type mice subjected to I/R without IPC treatment. Furthermore, AE1-329 significantly enhanced the I/R-induced activation of Akt, a pro-survival kinase. We demonstrated that the PGE2/EP4 system in the heart plays a critical role in the late phase of IPC, partly by augmenting Akt-mediated signaling. These findings clarify the mechanism of IPC and may contribute to the development of therapeutic strategies for ischemic heart disease.

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