PMID- 30948641 OWN - NLM STAT- MEDLINE DCOM- 20200325 LR - 20221207 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 116 IP - 17 DP - 2019 Apr 23 TI - VSMC-specific EP4 deletion exacerbates angiotensin II-induced aortic dissection by increasing vascular inflammation and blood pressure. PG - 8457-8462 LID - 10.1073/pnas.1902119116 [doi] AB - Prostaglandin E2 (PGE2) plays an important role in vascular homeostasis. Its receptor, E-prostanoid receptor 4 (EP4) is essential for physiological remodeling of the ductus arteriosus (DA). However, the role of EP4 in pathological vascular remodeling remains largely unknown. We found that chronic angiotensin II (AngII) infusion of mice with vascular smooth muscle cell (VSMC)-specific EP4 gene knockout (VSMC-EP4(-/-)) frequently developed aortic dissection (AD) with severe elastic fiber degradation and VSMC dedifferentiation. AngII-infused VSMC-EP4(-/-) mice also displayed more profound vascular inflammation with increased monocyte chemoattractant protein-1 (MCP-1) expression, macrophage infiltration, matrix metalloproteinase-2 and -9 (MMP2/9) levels, NADPH oxidase 1 (NOX1) activity, and reactive oxygen species production. In addition, VSMC-EP4(-/-) mice exhibited higher blood pressure under basal and AngII-infused conditions. Ex vivo and in vitro studies further revealed that VSMC-specific EP4 gene deficiency significantly increased AngII-elicited vasoconstriction of the mesenteric artery, likely by stimulating intracellular calcium release in VSMCs. Furthermore, EP4 gene ablation and EP4 blockade in cultured VSMCs were associated with a significant increase in MCP-1 and NOX1 expression and a marked reduction in alpha-SM actin (alpha-SMA), SM22alpha, and SM differentiation marker genes myosin heavy chain (SMMHC) levels and serum response factor (SRF) transcriptional activity. To summarize, the present study demonstrates that VSMC EP4 is critical for vascular homeostasis, and its dysfunction exacerbates AngII-induced pathological vascular remodeling. EP4 may therefore represent a potential therapeutic target for the treatment of AD. FAU - Xu, Hu AU - Xu H AD - Advanced Institute for Medical Sciences, Dalian Medical University, 116044 Dalian, China. FAU - Du, Shengnan AU - Du S AD - Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, 450001 Zhengzhou, China. FAU - Fang, Bingying AU - Fang B AD - Advanced Institute for Medical Sciences, Dalian Medical University, 116044 Dalian, China. FAU - Li, Chaojie AU - Li C AD - Advanced Institute for Medical Sciences, Dalian Medical University, 116044 Dalian, China. FAU - Jia, Xiao AU - Jia X AD - Biobank, Peking University Third Hospital, 100191 Beijing, China. FAU - Zheng, Senfeng AU - Zheng S AD - Advanced Institute for Medical Sciences, Dalian Medical University, 116044 Dalian, China. FAU - Wang, Sailun AU - Wang S AD - Advanced Institute for Medical Sciences, Dalian Medical University, 116044 Dalian, China. FAU - Li, Qingwei AU - Li Q AD - Advanced Institute for Medical Sciences, Dalian Medical University, 116044 Dalian, China. FAU - Su, Wen AU - Su W AD - Department of Pathology, Shenzhen University Medical Center, 518060 Shenzhen, China. AD - Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204. FAU - Wang, Nanping AU - Wang N AD - Advanced Institute for Medical Sciences, Dalian Medical University, 116044 Dalian, China. FAU - Zheng, Feng AU - Zheng F AD - Advanced Institute for Medical Sciences, Dalian Medical University, 116044 Dalian, China. FAU - Chen, Lihong AU - Chen L AD - Advanced Institute for Medical Sciences, Dalian Medical University, 116044 Dalian, China. FAU - Zhang, Xiaoyan AU - Zhang X AD - Advanced Institute for Medical Sciences, Dalian Medical University, 116044 Dalian, China; wserien@163.com jgustafs@central.uh.edu guanyf@dmu.edu.cn. FAU - Gustafsson, Jan-Ake AU - Gustafsson JA AD - Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204; wserien@163.com jgustafs@central.uh.edu guanyf@dmu.edu.cn. AD - Center for Innovative Medicine, Department of Biochemistry and Nutrition, Karolinska Institutet, 14186 Huddinge, Sweden. FAU - Guan, Youfei AU - Guan Y AD - Advanced Institute for Medical Sciences, Dalian Medical University, 116044 Dalian, China; wserien@163.com jgustafs@central.uh.edu guanyf@dmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190404 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Ptger4 protein, mouse) RN - 0 (Receptors, Prostaglandin E, EP4 Subtype) RN - 11128-99-7 (Angiotensin II) RN - K7Q1JQR04M (Dinoprostone) SB - IM MH - Aortic Dissection/*metabolism MH - Angiotensin II/*metabolism MH - Animals MH - Aorta/chemistry/metabolism MH - Aortic Aneurysm/metabolism MH - Blood Pressure/*physiology MH - Dinoprostone/metabolism MH - Female MH - Hypertension/metabolism MH - Inflammation/*metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Muscle, Smooth, Vascular/metabolism MH - *Receptors, Prostaglandin E, EP4 Subtype/genetics/metabolism MH - Vascular Remodeling/genetics PMC - PMC6486760 OTO - NOTNLM OT - EP4 OT - PGE2 OT - hypertension OT - inflammation OT - vascular remodeling COIS- The authors declare no conflict of interest. EDAT- 2019/04/06 06:00 MHDA- 2020/03/26 06:00 PMCR- 2019/10/04 CRDT- 2019/04/06 06:00 PHST- 2019/04/06 06:00 [pubmed] PHST- 2020/03/26 06:00 [medline] PHST- 2019/04/06 06:00 [entrez] PHST- 2019/10/04 00:00 [pmc-release] AID - 1902119116 [pii] AID - 201902119 [pii] AID - 10.1073/pnas.1902119116 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2019 Apr 23;116(17):8457-8462. doi: 10.1073/pnas.1902119116. Epub 2019 Apr 4.