The Role of Prostaglandin E2 Receptor EP4 Signaling in the Vascular Smooth Muscles

• Project/Area Number: 25860614
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Yokohama City University
• Principal Investigator: ICHIKAWA Yasuhiro 横浜市立大学, 医学研究科, 客員講師 (10555121)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: EP4 / 大動脈瘤 / 血管平滑筋 / MMP / 動脈瘤 / 平滑筋 / 弾性線維

Outline of Final Research Achievements

Elasticity contributes to mechanical properties of the arteries and loss of elastic properties exacerbates aortic aneurysms (AA). It is well known that prostaglandin E2 (PGE2) synthesis is enhanced in AA. We have demonstrated that the PGE2 receptor EP4 was abundantly expressed in smooth muscle cells (SMCs) from human AA tissues. We examined whether PGE2-EP4 signaling in SMCs decreases elasticity in the aorta. We generated mice with vascular smooth muscle-specific overexpression of human EP4 using the Cre-loxP system. After angiotensin II (ATII) infusion, however, the aorta of EP4TG were deformed and enlarged to a greater degree than that of EP4NTG. Further, elasicity was decreased in EP4TG than in EP4NTG. MMP-2 activity of EP4TG is higher than that of EP4NTG in the basal condition by gelatin zymography. MMP-9 activity was also abundant in EP4TG under ATII treatment. EP4 signaling in SMCs is suggested to be decreased aortic elasticity by promoting the degradation of elastic fibers.

Research Products

• [Journal Article] Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses (2014)
  • Author(s): Okumura S, Fujita T, Cai W, Jin M, Namekata I, Mototani Y, Jin H, Ohnuki Y, Tsuneoka Y, Kurotani R, Suita K, Kawakami Y, Hamaguchi S, Abe T, Kiyonari H, Tsunematsu T, Bai Y, Suzuki S, Hidaka Y, Umemura M, Ichikawa Y, Yokoyama U, Sato M, Ishikawa F, Izumi-Nakaseko H, Adachi-Akahane S, Tanaka H, Ishikawa Y.
  • Journal Title: J Clin Invest. Volume: ６ Pages: 2785-2801
  • Peer Reviewed
• [Journal Article] Decreased serum osmolality augments the closure of ductus arteriosus in neonates., (2014)
  • Author(s): Aoki R, Yokoyama U, Ichikawa Y, Kumagaya S, Ishiwata R, Fujita S, Umemura M, Fujita T, Minamisawa S, Iwasaki S, Nishimaki S, Seki Kazuo, Yokota S and Ishikawa Y
  • Journal Title: Cardiovasc Res Volume: 104 Pages: 326-336
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Three-Dimensional Multilayers of Smooth Muscle Cells Is a New Experimental Model for Studies of Vascular Elastic Fiber Formation, (2014)
  • Author(s): Ishiwata R, Yokoyama U, Ichikawa Y, Umemura M, Fujita T, Minamisawa S, Matsusaki M, Akashi M, Ishikawa Y.
  • Journal Title: Arteriosclerosis Volume: 233 Pages: 590-600
  • Peer Reviewed
• [Journal Article] Three-Dimensional Multilayers of Smooth Muscle Cells Is a New Experimental Model for Studies of Vascular Elastic Fiber Formation (2014)
  • Author(s): Ishiwata R, Yokoyama U, Ichikawa Y, Umemura M, Fujita T, Minamisawa S, Matsusaki M, Akashi M, Ishikawa Y.
  • Journal Title: Arteriosclerosis Volume: 233 Pages: 590-600
  • Peer Reviewed
• [Presentation] Prostaglandin E2 receptor EP4 signaling in vascular smooth muscle cells decreases aortic elasticity (2014)
  • Author(s): Ichikawa Y, Yokoyama U, Ishikawa Y,
  • Organizer: FASEB Experimental Biology
  • Place of Presentation: San Diego, CA、米国
  • Year and Date: 2014-04-23 – 2014-04-29
• [Presentation] Prostaglandin E2 Receptor EP4 Signaling in Vascular Smooth Muscle Decreased Elasticity of the Aorta (2013)
  • Author(s): Ichikawa Y, Yokoyama U, Iwamoto M, Yokota S, Minamisawa S, Ishikawa Y,
  • Organizer: AHA2013
  • Place of Presentation: Dallas, TX, アメリカ
• [Presentation] Decreased Serum Osmolality Augments the Closure of the Ductus Arteriosus in Neonates (2013)
  • Author(s): Yokoyama U, Aoki R, Ichikawa Y, Iwasaki S, Seki K, Nishimaki S, Yokota S, Minamisawa S, Ishikawa Y,
  • Organizer: AHA2013
  • Place of Presentation: Dallas, TX, アメリカ
• [Presentation] Anti-fibrotic Effect of Prostaglandin E2-EP4 in the Heart (2013)
  • Author(s): Ishiwata R, Yokoyama U, Inoue S, Ichikawa Y, Ishikawa Y,
  • Organizer: AHA2013
  • Place of Presentation: Dallas, TX, アメリカ
• [Remarks] 横浜市立大学医学部循環制御医学
  • URL: http://www-user.yokohama-cu.ac.jp/~seiri1/
• [Remarks] 横浜市立大学循環制御医学
  • URL: http://www-user.yokohama-cu.ac.jp/~seiri1/gyouseki.html