Expression of prostanoid receptors and induction of positive remodeling in vein grafts

Research Project

Project/Area Number	17K10766
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Cardiovascular surgery
Research Institution	Tokyo Medical University
Principal Investigator	NISHIBE TOSHIYA 東京医科大学, 医学部, 教授 (10261306)
Project Period (FY)	2017-04-01 – 2020-03-31
Project Status	Completed (Fiscal Year 2019)
Budget Amount *help	¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000) Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000) Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000) Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords	静脈グラフト / プロスタノイド / EP2 / IP / リモデリング / プロスタノイド受容体 / 移植・再生医療
Outline of Final Research Achievements	Previous studies on arterial and venous grafts have shown that prostanoids may prevent graft failure due to intimal thickening. However, its mechanism has not yet been clarified. We hypothesized based on the embryological findings of prostanoid receptors that prostanoid receptors are expressed in vascular smooth muscle cells (VSMCs) dedifferentiated during the process of vascular remodeling, and these receptors are involved in positive remodeling of arterial and venous grafts. In a rat autologous vein implantation model, the expression of EP2 and IP (prostacyclin receptor) mRNAs and proteins during graft remodeling was investigated using quantitative polymerase chain reaction and western blotting, respectively. The localization of EP2 and IP was also investigated by immunohistochemistry. We demonstrated that EP2 and IP were expressed in dedifferentiated VSMCs during the remodeling process, and this result suggested that these receptors may be involved in graft remodeling.
Academic Significance and Societal Importance of the Research Achievements	動脈・静脈グラフトを使用した血行再建術は虚血性心疾患や下肢閉塞性動脈硬化症などの動脈硬化性疾患に対する治療として広く行われているが、グラフト不全に基づく狭窄や閉塞の問題は解決されていない。薬剤投与や遺伝子導入による新生内膜肥厚の抑制に関する基礎・臨床研究が数多く報告されているが、中でも有効性が認められたもののひとつとしてプロスタノイドがある。本研究では血管リモデリングの過程でプロスタノイドの受容体であるEP2及びIPが脱分化した血管平滑筋細胞に過剰に発現していることを明らかにしたが、この結果はグラフト不全を予防する方法の確立につながるものであり、広く患者に恩恵を与えることに寄与すると考える。