Prostaglandin I ₂ Promotes Recruitment of Endothelial Progenitor Cells and Limits Vascular Remodeling

Abstract

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...

Eicosapentaenoic Acid (EPA) Reduces Cardiovascular Events: Relationship with the EPA/Arachidonic Acid Ratio

“…EPCs release PGI2, and their neoangiogenic activity depends on the production of endogenous PGI2 67) . EPCs are PGI2 receptor (IP)-expressing cells; PGI2 enhances the functions of EPCs (adhesion to the extracellular matrix, migration and the regulation of vascular remodeling) 68) and promotes neoangiogenesis, such as lumen formation, via the late differentiation of EPCs into endothelial cells 67) . These views are supported by the following observations.…”

Immortalized multipotent pericytes derived from the vasa vasorum in the injured vasculature. A cellular tool for studies of vascular remodeling and regeneration

“…24 A CCT was attached just beside the injured femoral artery. 23 Two weeks after the surgery, the collagen-layer on the CCT (CCT membrane) was removed.…”

Inflammation-related gene expression by lipid oxidation-derived products in the progression of atherosclerosis

“…Because of their opposed actions, the balance between these two bioactive lipids is known to be a critical factor causing a tendency to thrombosis. Moreover, it has been suggested that PGI 2 suppresses the development of vascular remodeling, due to its inhibitory actions on vascular SMC proliferation and on the platelet function [242] but also due to its regulatory role over endothelial progenitor cells, which are known to be the cells involved in reendothelialization, a process which limites vascular remodeling [243]. PGI 2 is also reported to play a role in the proangiogenic function of endothelial progenitor cells, consisting in proliferation of these cells and tube and capillary formation [244].…”