Inflammatory responses in the kidney lead to tubulointerstitial fibrosis, a common feature of chronic kidney diseases. Here we examined the role of prostaglandin E(2) (PGE(2)) in the development of tubulointerstitial fibrosis. In the kidneys of wild-type mice, unilateral ureteral obstruction leads to progressive tubulointerstitial fibrosis with macrophage infiltration and myofibroblast proliferation. This was accompanied by an upregulation of COX-2 and PGE(2) receptor subtype EP(4) mRNAs. In the kidneys of EP(4) gene knockout mice, however, obstruction-induced histological alterations were significantly augmented. In contrast, an EP(4)-specific agonist significantly attenuated these alterations in the kidneys of wild-type mice. The mRNAs for macrophage chemokines and profibrotic growth factors were upregulated in the kidneys of wild-type mice after ureteral obstruction. This was significantly augmented in the kidneys of EP(4)-knockout mice and suppressed by the EP(4) agonist but only in the kidneys of wild-type mice. Notably, COX-2 and MCP-1 proteins, as well as EP(4) mRNA, were localized in renal tubular epithelial cells after ureteral obstruction. In cultured renal fibroblasts, another EP(4)-specific agonist significantly inhibited PDGF-induced proliferation and profibrotic connective tissue growth factor production. Hence, an endogenous PGE(2)-EP(4) system in the tubular epithelium limits the development of tubulointerstitial fibrosis by suppressing inflammatory responses.

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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...

Introduction Atherosclerosis is fundamental pathological condition inducing severe ischemic diseases such as ischemic heart disease and stroke. New concept has been proposed that adventitial abnormalities including enhanced malformation of adventitial microvessel, vasa vasorum are associated with development and vulnerability of atherosclerotic plaque. However, the role of vasa vasorum malformation in vascular remodelling has not been fully clarified. We recently reported that Ninjurin1 (Ninj1) is critical adhesion molecule to associate pericytes (PCs) with endothelial (EC) tubes to form stabilized mature neovessels. The purpose of this study is to examine if formation of adventitial microvessels affects the vascular remodelling of injured vessels using PCs-specific Ninj1 deletion mouse model. Methods and results Deletion of Ninj1 gene in NG2-positive PCs was induced by tamoxifen (Tam)-treated NG2-CreER/Ninj1loxp mice (Ninj1KO, n=9). Tam-treated-NG2-CreER (n=4) or Tam-nontreated NG2-CreER/Ninj1loxp (n=5) mice were used as Control (Ct1 and Ct2 respectively). Femoral arteries were injured by insertion of coiled wire. After 4 weeks of surgery, blood vessels were stained by venous injection of FITC-lectin. Isolated femoral arteries were fixed with paraformaldehyde and decolorized with CUBIC reagent. Wire-mediated vessel injury induced intimal hyperplasia, as assessed by intima/media (I/M) ratio and accordingly grew microvessels in adventitia. Intimal hyperplasia in Ninj1KO were significantly enhanced compared to Controls. Although there was no significant difference in total length of adventitial microvessels among three groups, extravasation of FITC-lectin from adventitial microvessels were significantly enhanced in Ninj1KO. The number of infiltrated macrophages in adventitia were increased in Ninj1KO. Conclusion Deletion of Ninj1 in PCs contributes to formation of immature microvessels in adventitia of injured vasculature and to adventitial microbleeding, and subsequently enhances intimal hyperplasia. Ninj1 is an attractive target to normalize microvessels for anti-atherosclerotic therapy.