{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T19:09:39Z","timestamp":1791486579132,"version":"4.3.4"},"reference-count":68,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2026,7,6]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Atherothrombosis, which underlies most acute coronary syndromes and is driven by intraplaque thrombosis, preferentially occurs in regions of disturbed blood flow (d-flow). Although LATS1\/2 (large tumor suppressor kinases 1 and 2) are known regulators of endothelial mechanotransduction, the mechanisms by which d-flow connects endothelial senescence, proliferation, and intraplaque thrombosis remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We investigated endothelial cell (EC)-specific roles of\n                      <jats:italic toggle=\"yes\">Lats1\/2<\/jats:italic>\n                      using inducible EC-specific knockout mice in a partial carotid ligation model. Spatial multiomics of human and mouse plaques was performed using imaging mass cytometry, COMET sequential immunofluorescence, and spatial metabolomics.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Tamoxifen-induced deletion of both Lats1 and Lats2 (homozygous) in ECs caused fatal edema and increased vascular permeability. In contrast,\n                      <jats:italic toggle=\"yes\">Lats1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">het<\/jats:italic>\n                        (\n                      <\/jats:sup>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u00b1<\/jats:italic>\n                        )\n                      <\/jats:sup>\n                      \/\n                      <jats:italic toggle=\"yes\">Lats2<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">homo<\/jats:italic>\n                        (\n                      <\/jats:sup>\n                      <jats:sup>\u2212\/\u2212)<\/jats:sup>\n                      -EC-specific knockout mice survived and developed spontaneous atherothrombotic plaques with neovascularization. Spatial proteomics revealed that LATS1\/2 loss induced a senescence-associated stemness phenotype driven by CD38 upregulation. Spatial metabolomics showed sulfite and taurine accumulation, indicating SUOX (sulfite oxidase) deficiency. CD38 suppressed SUOX, demonstrated a switch into the reverse mode of mitochondrial complex V, increased succinate dehydrogenase activity, and promoted ATP consumption. Despite ATP depletion, glutamate metabolism and the citric acid cycle flux increased, sustaining EC proliferation under energetic stress. This senescence-associated stemness state promoted both proliferation and senescence, leading to fragile, leaky neovessels and intraplaque thrombotic lesions. Pharmacological CD38 inhibition attenuated these phenotypes. Similar EC states were observed in human plaques.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      Loss of\n                      <jats:italic toggle=\"yes\">Lats1\/2<\/jats:italic>\n                      in ECs induces a CD38-associated senescence-associated stemness-like phenotype that promotes intraplaque thrombosis through mitochondrial metabolic reprogramming, including changes consistent with reverse-mode operation of mitochondrial complex V. These findings define a mechanistic link between disturbed flow, endothelial metabolic reprogramming, and intraplaque thrombosis and hemorrhage.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.125.327427","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T09:00:41Z","timestamp":1779872441000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["LATS1\/2-CD38 Metabolic Rewiring Links Senescence to Intraplaque Thrombosis"],"prefix":"10.1161","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7516-7647","authenticated-orcid":true,"given":"Sivareddy","family":"Kotla","sequence":"first","affiliation":[{"name":"Department of Cardiology (S.K., J.L., K.A.K., V.S.K.S., O.H., G.F.M., L.A.R., M.I., K.C.T.S., J.H.K., K.C.O.-M., K.N.M.-R., A.D., K.F., N.L.P., E.K., Y.J.G., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1182-9653","authenticated-orcid":true,"given":"Jonghae","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Cardiology (S.K., J.L., K.A.K., V.S.K.S., O.H., G.F.M., L.A.R., M.I., K.C.T.S., J.H.K., K.C.O.-M., K.N.M.-R., A.D., K.F., N.L.P., E.K., Y.J.G., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston."},{"name":"Department of Pediatrics-Research (J.L., K.L.S.), The University of Texas MD Anderson Cancer Center, Houston."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung Ae","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Cardiology (S.K., J.L., K.A.K., V.S.K.S., O.H., G.F.M., L.A.R., M.I., K.C.T.S., J.H.K., K.C.O.-M., K.N.M.-R., A.D., K.F., N.L.P., E.K., Y.J.G., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3539-9210","authenticated-orcid":true,"given":"Weiqing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX (W.C., S.L., G.W., N.-T.L., J.P.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2445-0396","authenticated-orcid":true,"given":"Venkata Subrahmanya Kumar","family":"Samanthapudi","sequence":"additional","affiliation":[{"name":"Department of Cardiology (S.K., J.L., K.A.K., V.S.K.S., O.H., G.F.M., L.A.R., M.I., K.C.T.S., J.H.K., K.C.O.-M., K.N.M.-R., A.D., K.F., N.L.P., E.K., Y.J.G., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5304-585X","authenticated-orcid":true,"given":"Oanh","family":"Hoang","sequence":"additional","affiliation":[{"name":"Department of Cardiology (S.K., J.L., K.A.K., V.S.K.S., O.H., G.F.M., L.A.R., M.I., K.C.T.S., J.H.K., K.C.O.-M., K.N.M.-R., A.D., K.F., N.L.P., E.K., Y.J.G., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4048-2013","authenticated-orcid":true,"given":"Gilbert F.","family":"Mejia","sequence":"additional","affiliation":[{"name":"Department of Cardiology (S.K., J.L., K.A.K., V.S.K.S., O.H., G.F.M., L.A.R., M.I., K.C.T.S., J.H.K., K.C.O.-M., K.N.M.-R., A.D., K.F., N.L.P., E.K., Y.J.G., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7809-2046","authenticated-orcid":true,"given":"Shengyu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX (W.C., S.L., G.W., N.-T.L., J.P.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3706-6906","authenticated-orcid":true,"given":"Hani","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Section of Benign Hematology, The University of Texas MD Anderson Cancer Center, Houston (H.L., M.S.C., V.A.-K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1491-8528","authenticated-orcid":true,"given":"Aijun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Bioenergetics, Houston Methodist Research Institute, TX (A.Z., D.J.H.)."},{"name":"Department of Medicine, Houston Methodist, Weill Cornell Medicine Affiliate, TX (A.Z., D.J.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9992-8356","authenticated-orcid":true,"given":"Min Soon","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Section of Benign Hematology, The University of Texas MD Anderson Cancer Center, Houston (H.L., M.S.C., V.A.-K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1675-0514","authenticated-orcid":true,"given":"Keri L.","family":"Schadler","sequence":"additional","affiliation":[{"name":"Department of Pediatrics-Research (J.L., K.L.S.), The University of Texas MD Anderson Cancer Center, Houston."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9151-3345","authenticated-orcid":true,"given":"Luis Antonio","family":"Rivera","sequence":"additional","affiliation":[{"name":"Department of Cardiology (S.K., J.L., K.A.K., V.S.K.S., O.H., G.F.M., L.A.R., M.I., K.C.T.S., J.H.K., K.C.O.-M., K.N.M.-R., A.D., K.F., N.L.P., E.K., Y.J.G., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Imanishi","sequence":"additional","affiliation":[{"name":"Department of Cardiology (S.K., J.L., K.A.K., V.S.K.S., O.H., G.F.M., L.A.R., M.I., K.C.T.S., J.H.K., K.C.O.-M., K.N.M.-R., A.D., K.F., N.L.P., E.K., Y.J.G., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kay Carlene","family":"Tavares Samperio","sequence":"additional","affiliation":[{"name":"Department of Cardiology (S.K., J.L., K.A.K., V.S.K.S., O.H., G.F.M., L.A.R., M.I., K.C.T.S., J.H.K., K.C.O.-M., K.N.M.-R., A.D., K.F., N.L.P., E.K., Y.J.G., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston."},{"name":"Instituto Tecnol\u00f3gico y de Estudios Superiores de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Le\u00f3n, M\u00e9xico (J.H.K., K.C.O.-M., K.C.T.S., K.N.M.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8526-1315","authenticated-orcid":true,"given":"Jung Hyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Cardiology (S.K., J.L., K.A.K., V.S.K.S., O.H., G.F.M., L.A.R., M.I., K.C.T.S., J.H.K., K.C.O.-M., K.N.M.-R., A.D., K.F., N.L.P., E.K., Y.J.G., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston."},{"name":"Instituto Tecnol\u00f3gico y de Estudios Superiores de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Le\u00f3n, M\u00e9xico (J.H.K., K.C.O.-M., K.C.T.S., 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of Texas MD Anderson Cancer Center, Houston."},{"name":"Instituto Tecnol\u00f3gico y de Estudios Superiores de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Le\u00f3n, M\u00e9xico (J.H.K., K.C.O.-M., K.C.T.S., K.N.M.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6147-9591","authenticated-orcid":true,"given":"Anita","family":"Deswal","sequence":"additional","affiliation":[{"name":"Department of Cardiology (S.K., J.L., K.A.K., V.S.K.S., O.H., G.F.M., L.A.R., M.I., K.C.T.S., J.H.K., K.C.O.-M., K.N.M.-R., A.D., K.F., N.L.P., E.K., Y.J.G., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0033-9138","authenticated-orcid":true,"given":"John P.","family":"Cooke","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX (W.C., S.L., G.W., N.-T.L., J.P.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9267-9190","authenticated-orcid":true,"given":"Keigi","family":"Fujiwara","sequence":"additional","affiliation":[{"name":"Department of Cardiology (S.K., J.L., K.A.K., V.S.K.S., O.H., G.F.M., L.A.R., M.I., K.C.T.S., J.H.K., K.C.O.-M., K.N.M.-R., A.D., K.F., N.L.P., E.K., Y.J.G., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7565-1797","authenticated-orcid":true,"given":"Nicolas L.","family":"Palaskas","sequence":"additional","affiliation":[{"name":"Department of Cardiology (S.K., J.L., K.A.K., V.S.K.S., O.H., G.F.M., L.A.R., M.I., K.C.T.S., J.H.K., K.C.O.-M., K.N.M.-R., A.D., K.F., N.L.P., E.K., Y.J.G., J.-I.A.), The University of Texas MD Anderson Cancer Center, 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Houston."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajneesh","family":"Pathania","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine &amp; Surgery (R.P.), The University of Texas MD Anderson Cancer Center, Houston."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9131-4862","authenticated-orcid":true,"given":"Craig","family":"Morrell","sequence":"additional","affiliation":[{"name":"Department of Medicine, Aab Cardiovascular Research Institute (C.M.), University of Rochester, NY."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0385-7774","authenticated-orcid":true,"given":"Philip L.","family":"Lorenzi","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Computational Biology (P.L.L., L.T., I.M.), The University of Texas MD Anderson Cancer Center, Houston."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Computational Biology (P.L.L., L.T., I.M.), The University of Texas MD Anderson Cancer Center, Houston."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7729-8122","authenticated-orcid":true,"given":"Iqbal","family":"Mahmud","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Computational Biology (P.L.L., L.T., I.M.), The University of Texas MD Anderson Cancer Center, Houston."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9541-7244","authenticated-orcid":true,"given":"Nordin M.J.","family":"Hanssen","sequence":"additional","affiliation":[{"name":"Department of (Experimental) Vascular and Internal Medicine, Amsterdam UMC, the Netherlands (N.M.J.H.)."},{"name":"Diabeter Centrum Amsterdam, the Netherlands (N.M.J.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2911-1284","authenticated-orcid":true,"given":"Vahid","family":"Afshar-Kharghan","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Section of Benign Hematology, The University of Texas MD Anderson Cancer Center, Houston (H.L., M.S.C., V.A.-K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2481-2746","authenticated-orcid":true,"given":"Dale J","family":"Hamilton","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Bioenergetics, Houston Methodist Research Institute, TX (A.Z., D.J.H.)."},{"name":"Department of Medicine, Houston Methodist, Weill Cornell Medicine Affiliate, TX (A.Z., D.J.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7748-4942","authenticated-orcid":true,"given":"Laurent","family":"Yvan-Charvet","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (Inserm) U1065, Universit\u00e9 C\u00f4te d\u2019Azur, Centre M\u00e9diterran\u00e9en de M\u00e9decine Mol\u00e9culaire (C3M), F\u00e9d\u00e9ration Hospitalo-Universitaire (FHU) Oncoage, IHU Respiratory Health, Environment and Ageing (RespirERA), Nice, France (L.Y.-C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1555-4834","authenticated-orcid":true,"given":"Eduardo N.","family":"Chini","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, FL (E.N.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6675-4559","authenticated-orcid":true,"given":"Joerg","family":"Herrmann","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (J.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hernan G.","family":"Vasquez","sequence":"additional","affiliation":[{"name":"Michael E. Debakey Department of Surgery, Baylor College of Medicine, Houston, TX (H.G.V., Y.H.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4119-115X","authenticated-orcid":true,"given":"Ying H.","family":"Shen","sequence":"additional","affiliation":[{"name":"Michael E. Debakey Department of Surgery, Baylor College of Medicine, Houston, TX (H.G.V., Y.H.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7842-9857","authenticated-orcid":true,"given":"James F.","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (J.F.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haodong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Anatomic Pathology, Wake Forest University School of Medicine, Winston-Salem, NC (H.X.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8000-5754","authenticated-orcid":true,"given":"Erin H","family":"Seeley","sequence":"additional","affiliation":[{"name":"Department of Chemistry, the University of Texas at Austin 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