{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T15:37:35Z","timestamp":1790350655656,"version":"4.1.0"},"reference-count":66,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2024,8,30]]},"abstract":"\n BACKGROUND:<\/jats:title>\n \n Prostaglandin I\n 2<\/jats:sub>\n synthesized by endothelial COX (cyclooxygenase) evokes potent vasodilation in some blood vessels but is paradoxically responsible for endothelium-dependent constriction (EDC) in others. Prostaglandin I\n 2<\/jats:sub>\n production and EDC may be enhanced in diseases such as hypertension. However, how PGIS (prostaglandin I\n 2<\/jats:sub>\n synthase) deficiency affects EDC and how this is implicated in the consequent cardiovascular pathologies remain largely unknown.\n <\/jats:p>\n <\/jats:sec>\n \n METHODS:<\/jats:title>\n \n Experiments were performed with wild-type,\n Pgis<\/jats:italic>\n knockout (\n Pgis<\/jats:italic>\n \n \u2212<\/jats:italic>\n \/\n \u2212<\/jats:italic>\n <\/jats:sup>\n ) and\n Pgis<\/jats:italic>\n \/thromboxane-prostanoid receptor gene (\n Tp<\/jats:italic>\n ) double knockout (\n Pgis<\/jats:italic>\n \n \u2212<\/jats:italic>\n \/\n \u2212<\/jats:italic>\n <\/jats:sup>\n Tp<\/jats:italic>\n \n \u2212<\/jats:italic>\n \/\n \u2212<\/jats:italic>\n <\/jats:sup>\n ) mice and\n Pgis<\/jats:italic>\n \n \u2212<\/jats:italic>\n \/\n \u2212<\/jats:italic>\n <\/jats:sup>\n mice transplanted with unfractionated wild-type or\n Cox-1<\/jats:italic>\n \n \u2212<\/jats:italic>\n \/\n \u2212<\/jats:italic>\n <\/jats:sup>\n bone marrow cells, as well as human umbilical arteries. COX-derived prostanoids were measured by high-performance liquid chromatography-mass spectrometry. Vasomotor responses of distinct types of arteries were assessed by isometric force measurement. Parameters of hypertension, vascular remodeling, and cardiac hypertrophy in mice at different ages were monitored.\n <\/jats:p>\n <\/jats:sec>\n \n RESULTS:<\/jats:title>\n \n PGF\n 2\u03b1<\/jats:sub>\n , PGE\n 2<\/jats:sub>\n , and a trace amount of PGD\n 2<\/jats:sub>\n , but not thromboxane A\n 2<\/jats:sub>\n (TxA\n 2<\/jats:sub>\n ), were produced in response to acetylcholine in\n Pgis<\/jats:italic>\n \n \u2212<\/jats:italic>\n \/\n \u2212<\/jats:italic>\n <\/jats:sup>\n or PGIS-inhibited arteries. PGIS deficiency resulted in exacerbation or occurrence of EDC ex vivo and in vivo. Endothelium-dependent hyperpolarization was unchanged, but phosphorylation levels of eNOS (endothelial nitric oxide synthase) at Ser1177 and Thr495 were altered and NO production and the NO-dependent relaxation evoked by acetylcholine were remarkably reduced in\n Pgis<\/jats:italic>\n \n \u2212<\/jats:italic>\n \/\n \u2212<\/jats:italic>\n <\/jats:sup>\n aortas.\n Pgis<\/jats:italic>\n \n \u2212<\/jats:italic>\n \/\n \u2212<\/jats:italic>\n <\/jats:sup>\n mice developed high blood pressure and vascular remodeling at 16 to 17 weeks and subsequently cardiac hypertrophy at 24 to 26 weeks. Meanwhile, blood pressure and cardiac parameters remained normal at 8 to 10 weeks. Additional ablation of TP (TxA\n 2<\/jats:sub>\n receptor) not only restrained EDC and the downregulation of NO signaling in\n Pgis<\/jats:italic>\n \n \u2212<\/jats:italic>\n \/\n \u2212<\/jats:italic>\n <\/jats:sup>\n mice but also ameliorated the cardiovascular abnormalities. Stimulation of\n Pgis<\/jats:italic>\n \n \u2212<\/jats:italic>\n \/\n \u2212<\/jats:italic>\n <\/jats:sup>\n vessels with acetylcholine in the presence of platelets led to increased TxA\n 2<\/jats:sub>\n generation. COX-1 disruption in bone marrow\u2013derived cells failed to affect the development of high blood pressure and vascular remodeling in\n Pgis<\/jats:italic>\n \n \u2212<\/jats:italic>\n \/\n \u2212<\/jats:italic>\n <\/jats:sup>\n mice though it largely suppressed the increase of plasma TxB\n 2<\/jats:sub>\n (TxA\n 2<\/jats:sub>\n metabolite) level.\n <\/jats:p>\n <\/jats:sec>\n \n CONCLUSIONS:<\/jats:title>\n \n Our study demonstrates that the non-TxA\n 2<\/jats:sub>\n prostanoids\/TP axis plays an essential role in mediating the augmentation of EDC and cardiovascular disorders when PGIS is deficient, suggesting TP as a promising therapeutic target in diseases associated with PGIS insufficiency.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/circresaha.124.324924","type":"journal-article","created":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T05:08:24Z","timestamp":1722402504000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":17,"title":["Prostacyclin Synthase Deficiency Leads to Exacerbation or Occurrence of Endothelium-Dependent Contraction and Causes Cardiovascular Disorders Mainly via the Non-TxA\n 2<\/sub>\n Prostanoids\/TP Axis"],"prefix":"10.1161","volume":"135","author":[{"given":"Jiahui","family":"Ge","sequence":"first","affiliation":[{"name":"Cardiovascular Research Center (J.G., Yingbi Zhou, K.X., J.L., X.C., G.Y., X.S., Y.X., D.H., B.L.), Shantou University Medical College, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3098-404X","authenticated-orcid":true,"given":"Yingbi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center (J.G., Yingbi Zhou, K.X., J.L., X.C., G.Y., X.S., Y.X., D.H., B.L.), Shantou University Medical College, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Li","sequence":"additional","affiliation":[{"name":"Bio-Analytical Laboratory (H. 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Luo, W.L.), Shantou University Medical College, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruhui","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Gynaecology and Obstetrics, First Affiliated Hospital, Shantou University Medical College, China (R.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4622-9025","authenticated-orcid":true,"given":"Kaiqi","family":"Xie","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center (J.G., Yingbi Zhou, K.X., J.L., X.C., G.Y., X.S., Y.X., D.H., B.L.), Shantou University Medical College, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2447-3876","authenticated-orcid":true,"given":"Jing","family":"Leng","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center (J.G., Yingbi Zhou, K.X., J.L., X.C., G.Y., X.S., Y.X., D.H., B.L.), Shantou University Medical College, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xijian","family":"Chen","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center (J.G., Yingbi Zhou, K.X., J.L., X.C., G.Y., X.S., Y.X., D.H., B.L.), Shantou University Medical College, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Yu","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center (J.G., Yingbi Zhou, K.X., J.L., X.C., G.Y., X.S., Y.X., D.H., B.L.), Shantou University Medical College, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinya","family":"Shi","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center (J.G., Yingbi Zhou, K.X., J.L., X.C., G.Y., X.S., Y.X., D.H., B.L.), Shantou University Medical College, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yineng","family":"Xu","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center (J.G., Yingbi Zhou, K.X., J.L., X.C., G.Y., X.S., Y.X., D.H., B.L.), Shantou University Medical College, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"He","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center (J.G., Yingbi Zhou, K.X., J.L., X.C., G.Y., X.S., Y.X., D.H., B.L.), Shantou University Medical College, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pi","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Preventive Medicine (P.G.), Shantou University Medical College, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongyin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Bio-Analytical Laboratory (H. 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