{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T10:51:27Z","timestamp":1791197487692,"version":"4.1.0"},"reference-count":70,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2023,10,13]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>In developmental and pathological tissues, nascent vessel networks generated by angiogenesis require further pruning\/regression to delete nonfunctional endothelial cells (ECs) by apoptosis and migration. Mechanisms underlying EC apoptosis during vessel pruning remain elusive. TMEM215 (transmembrane protein 215) is an endoplasmic reticulum\u2013located, 2-pass transmembrane protein. We have previously demonstrated that TMEM215 knockdown in ECs leads to cell death, but its physiological function and mechanism are unclear.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              We characterized the role and mechanism of TMEM215 in EC apoptosis using human umbilical vein endothelial cells by identifying its interacting proteins with immunoprecipitation-mass spectrometry. The physiological function of TMEM215 in ECs was assessed by establishing a conditional knockout mouse strain. The role of TMEM215 in pathological angiogenesis was evaluated by tumor and choroidal neovascularization models. We also tried to evaluate its translational value by delivering a\n              <jats:italic>Tmem215<\/jats:italic>\n              small interfering RNA (siRNA) using nanoparticles in vivo.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              <jats:italic>TMEM215<\/jats:italic>\n              knockdown in ECs induced apoptotic cell death. We identified the chaperone BiP as a binding partner of TMEM215, and TMEM215 forms a complex with and facilitates the interaction of BiP (binding immunoglobin protein) with the BH (BCL-2 [B-cell lymphoma 2] homology) 3-only proapoptotic protein BIK (BCL-2 interacting killer).\n              <jats:italic>TMEM215<\/jats:italic>\n              knockdown triggered apoptosis in a BIK-dependent way and was abrogated by BCL-2. Notably,\n              <jats:italic>TMEM215<\/jats:italic>\n              knockdown increased the number and diminished the distance of mitochondria-associated endoplasmic reticulum membranes and increased mitochondrial calcium influx. Inhibiting mitochondrial calcium influx by blocking the IP\n              <jats:sub>3<\/jats:sub>\n              R (inositol 1,4,5-trisphosphate receptor) or MCU (mitochondrial calcium uniporter) abrogated\n              <jats:italic>TMEM215<\/jats:italic>\n              knockdown\u2013induced apoptosis.\n              <jats:italic>TMEM215<\/jats:italic>\n              expression in ECs was induced by physiological laminar shear stress via\n              <jats:italic>EZH2<\/jats:italic>\n              downregulation. In EC-specific\n              <jats:italic>Tmem215<\/jats:italic>\n              knockout mice, induced\n              <jats:italic>Tmem215<\/jats:italic>\n              depletion impaired the regression of retinal vasculature characterized by reduced vessel density, increased empty basement membrane sleeves, and increased EC apoptosis. Moreover, EC-specific\n              <jats:italic>Tmem215<\/jats:italic>\n              ablation inhibited tumor growth with disrupted vasculature. However,\n              <jats:italic>Tmem215<\/jats:italic>\n              ablation in adult mice attenuated lung metastasis, consistent with reduced\n              <jats:italic>Vcam1<\/jats:italic>\n              expression. Administration of nanoparticles carrying\n              <jats:italic>Tmem215<\/jats:italic>\n              siRNA also inhibited tumor growth and choroidal neovascularization injury.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>\n              <jats:italic>TMEM215<\/jats:italic>\n              , which is induced by blood flow-derived shear stress via downregulating\n              <jats:italic>EZH2<\/jats:italic>\n              , protects ECs from BIK-triggered mitochondrial apoptosis mediated by calcium influx through mitochondria-associated ER membranes during vessel pruning, thus providing a novel target for antiangiogenic therapy.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.123.322686","type":"journal-article","created":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T09:00:19Z","timestamp":1695718819000},"page":"739-757","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":31,"title":["TMEM215 Prevents Endothelial Cell Apoptosis in Vessel Regression by Blunting BIK-Regulated ER-to-Mitochondrial Ca Influx"],"prefix":"10.1161","volume":"133","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1552-2923","authenticated-orcid":true,"given":"Peiran","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology (P.Z., X.Y., X.Z., Y.L., X.F., Z.Y., J.Z., X.X., L.L., H.H.), Tangdu Hospital, Fourth Military Medical University, Xi\u2019an, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5649-5012","authenticated-orcid":true,"given":"Xianchun","family":"Yan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology (P.Z., X.Y., X.Z., Y.L., X.F., Z.Y., J.Z., X.X., L.L., H.H.), Tangdu Hospital, Fourth Military Medical University, Xi\u2019an, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1199-988X","authenticated-orcid":true,"given":"Xiaoyan","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology (P.Z., X.Y., X.Z., Y.L., X.F., Z.Y., J.Z., X.X., L.L., H.H.), Tangdu Hospital, Fourth Military Medical University, Xi\u2019an, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1514-1997","authenticated-orcid":true,"given":"Yuan","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology (P.Z., X.Y., X.Z., Y.L., X.F., Z.Y., J.Z., X.X., L.L., H.H.), Tangdu Hospital, Fourth Military Medical University, Xi\u2019an, China."},{"name":"The Affiliated Northwest Women\u2019s and Children\u2019s Hospital of Xi\u2019an Jiaotong University Health Science Center, China (Y.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingxing","family":"Feng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology (P.Z., X.Y., X.Z., Y.L., X.F., Z.Y., J.Z., X.X., L.L., H.H.), Tangdu Hospital, Fourth Military Medical University, Xi\u2019an, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9030-2074","authenticated-orcid":true,"given":"Ziyan","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology (P.Z., X.Y., X.Z., Y.L., X.F., Z.Y., J.Z., X.X., L.L., H.H.), Tangdu Hospital, Fourth Military Medical University, Xi\u2019an, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1718-9527","authenticated-orcid":true,"given":"Jiayulin","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology (P.Z., X.Y., X.Z., Y.L., X.F., Z.Y., J.Z., X.X., L.L., H.H.), Tangdu Hospital, Fourth Military Medical University, Xi\u2019an, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyuan","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology (P.Z., X.Y., X.Z., Y.L., X.F., Z.Y., J.Z., X.X., L.L., H.H.), Tangdu Hospital, Fourth Military Medical University, Xi\u2019an, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4525-8537","authenticated-orcid":true,"given":"Qijun","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Shenzhen People\u2019s Hospital, China (Q.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9941-8682","authenticated-orcid":true,"given":"Liang","family":"Liang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology (P.Z., X.Y., X.Z., Y.L., X.F., Z.Y., J.Z., X.X., L.L., H.H.), Tangdu Hospital, Fourth Military Medical University, Xi\u2019an, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1872-9700","authenticated-orcid":true,"given":"Hua","family":"Han","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology (P.Z., X.Y., X.Z., Y.L., X.F., Z.Y., J.Z., X.X., L.L., H.H.), Tangdu Hospital, Fourth Military Medical University, Xi\u2019an, China."},{"name":"Department of Gastroenterology (H.H.), Tangdu Hospital, Fourth Military Medical University, Xi\u2019an, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10144"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2015.06.004"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-017-2577-y"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.119.316071"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1002125"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1002126"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2018.29"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2021.174021"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-020-03738-x"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.090099"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI122767"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.04.036"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2017.186"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a036319"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22073730"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom12020162"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-022-04942-2"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells10030657"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16241"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0907555106"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.622514"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0408352102"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0178198"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.13190"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2009.40"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.4.1570-1581.2004"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600592"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M500800200"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00975-w"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2017.05.015"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-4594"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0911991107"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.212944"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiomech.2021.110917"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2021.05.005"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-007-9065-1"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2022.108152"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-019-0239-5"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.27641"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00738-7"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.86.2.185"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-015-9485-2"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.112.191098"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11606"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1530\/REP-09-0283"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03351-7"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells11233922"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19041057"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.3390\/nano10071248"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2016.07.008"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1111\/cas.15323"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00616.2005"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63273-7"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02883"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4036"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/9179111"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cossms.2020.100872"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.21966"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00047.2018"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.06.007"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2009.01.005"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.11.010"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.08.036"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09002"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2021.07.023"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00510.2009"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29834"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2023.121828"},{"key":"e_1_3_3_70_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI164508"},{"key":"e_1_3_3_71_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2022.03.003"}],"container-title":["Circulation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCRESAHA.123.322686","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T04:29:42Z","timestamp":1715574582000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCRESAHA.123.322686"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,13]]},"references-count":70,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2023,10,13]]}},"alternative-id":["10.1161\/CIRCRESAHA.123.322686"],"URL":"https:\/\/doi.org\/10.1161\/circresaha.123.322686","relation":{},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,13]]},"assertion":[{"value":"2023-02-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-26","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}