Online ISSN: 2187-2988 Print ISSN: 0911-1794
特定非営利活動法人日本小児循環器学会 Japanese Society of Pediatric Cardiology and Cardiac Surgery
Pediatric Cardiology and Cardiac Surgery 32(1): 2-8 (2016)


動脈管閉鎖の分子機序解明にむけてMolecular Mechanisms for Ductus Arteriosus Closure

東京慈恵会医科大学細胞生理学講座Department of Cell Physiology, Jikei University School of Medicine, Tokyo, Japan

受付日:2015年11月16日Received: November 16, 2015
受理日:2015年12月24日Accepted: December 24, 2015
発行日:2016年1月1日Published: January 1, 2016


Ductus arteriosus (DA) is essential for fetal circulation and closes immediately after birth. DA closure occurs through the following two mechanisms: 1) vascular constriction mainly due to an increase in blood oxygen level and a decrease in prostaglandin E2 (PGE2) and 2) structural remodeling, resulting in easy closure of DA. In addition to the well-known vasodilator action of PGE2, we found that the PGE2-EP4 signal plays a critical role in characterizing the DA structure, such as the formation of intimal thickening and the disassembly of the internal elastic lamina and loss of elastic fiber in the medial layer. PGE2-EP4-adenylyl cyclase type 6-cyclic AMP signaling during gestation induces intimal thickening by activating both protein kinase A and Epac. Furthermore, the PGE2-EP4 signal inhibits elastogenesis by degrading lysyl oxidase, a key enzyme of elastin cross-linking, through the c-Src-PLCγ pathway. Thus, the PGE2-EP4 signal has multiple roles in vasodilation and vascular remodeling of the DA. Our study highlights the importance of understanding DA vascular remodeling better to encourage the design and development of novel pharmacological treatments for patients with patent DA or DA-dependent congenital heart diseases.

Key words: ductus arteriosus; vascular structure; intimal thickening; elastic fiber; fetal circulation

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