{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:10:53Z","timestamp":1792519853817,"version":"4.5.0"},"reference-count":82,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Peripheral ischemia caused by peripheral artery disease is associated with systemic inflammation, which may aggravate underlying comorbidities such as atherosclerosis and heart failure. However, the mechanisms of increased inflammation and inflammatory cell production in patients with peripheral artery disease remain poorly understood.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              We used peripheral blood collected from patients with peripheral artery disease and performed hind limb ischemia (HI) in\n              <jats:italic>Apoe<\/jats:italic>\n              <jats:sup>\n                <jats:italic>\u2212\/\u2212<\/jats:italic>\n              <\/jats:sup>\n              mice fed a Western diet and C57BL\/6J mice with a standard laboratory diet. Bulk and single-cell RNA sequencing analysis, whole-mount microscopy, and flow cytometry were performed to analyze hematopoietic stem and progenitor cell (HSPC) proliferation, differentiation, and relocation.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              We observed augmented numbers of leukocytes in the blood of patients with peripheral artery disease and\n              <jats:italic>Apoe<\/jats:italic>\n              <jats:sup>\n                <jats:italic>\u2212\/\u2212<\/jats:italic>\n              <\/jats:sup>\n              mice with HI. RNA sequencing and whole-mount imaging of the bone marrow revealed HSPC migration into the vascular niche from the osteoblastic niche and their exaggerated proliferation and differentiation. Single-cell RNA sequencing demonstrated alterations in the genes responsible for inflammation, myeloid cell mobilization, and HSPC differentiation after HI. Heightened inflammation in\n              <jats:italic>Apoe<\/jats:italic>\n              <jats:sup>\n                <jats:italic>\u2212\/\u2212<\/jats:italic>\n              <\/jats:sup>\n              mice after HI aggravated atherosclerosis. Surprisingly, bone marrow HSPCs expressed higher amounts of the receptors for IL (interleukin)-1 and IL-3 after HI. Concomitantly, the promoters of\n              <jats:italic>Il1r1<\/jats:italic>\n              and\n              <jats:italic>Il3rb<\/jats:italic>\n              had augmented H3K4me3 and H3K27ac marks after HI. Genetic and pharmacological inhibition of these receptors resulted in suppressed HSPC proliferation, reduced leukocyte production, and ameliorated atherosclerosis.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Our findings demonstrate increased inflammation, HSPC abundance in the vascular niches of the bone marrow, and elevated IL-3Rb and IL-1R1 (IL-1 receptor 1) expression in HSPC following HI. Furthermore, the IL-3Rb and IL-1R1 signaling plays a pivotal role in HSPC proliferation, leukocyte abundance, and atherosclerosis aggravation after HI.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.123.318956","type":"journal-article","created":{"date-parts":[[2023,3,9]],"date-time":"2023-03-09T10:00:55Z","timestamp":1678356055000},"page":"889-906","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":20,"title":["Peripheral Ischemia Imprints Epigenetic Changes in Hematopoietic Stem Cells to Propagate Inflammation and Atherosclerosis"],"prefix":"10.1161","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8987-0050","authenticated-orcid":true,"given":"Emilie","family":"Coppin","sequence":"first","affiliation":[{"name":"Department of Regeneration in Hematopoiesis, Institute for Immunology, TU Dresden, Germany (E.C.)."},{"name":"Immunology of Aging, Leibniz Institute on Aging\u2013Fritz Lipmann Institute, Jena, Germany (E.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5846-337X","authenticated-orcid":true,"given":"Xinyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China (X.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8228-6529","authenticated-orcid":true,"given":"Lee","family":"Ohayon","sequence":"additional","affiliation":[{"name":"Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute (L.O., E.J., A.D., E.C.-P., P.J.P., P.D.), University of Pittsburgh, PA."},{"name":"Department of Bioengineering, Swanson School of Engineering (L.O., P.D.), University of Pittsburgh, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8857-9357","authenticated-orcid":true,"given":"Ebin","family":"Johny","sequence":"additional","affiliation":[{"name":"Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute (L.O., E.J., A.D., E.C.-P., P.J.P., P.D.), University of Pittsburgh, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankush","family":"Dasari","sequence":"additional","affiliation":[{"name":"Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute (L.O., E.J., A.D., E.C.-P., P.J.P., P.D.), University of Pittsburgh, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang H.","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, the Netherlands (K.H.Z., L.S., E.S.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lotte","family":"Stiekema","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, the Netherlands (K.H.Z., L.S., E.S.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenia","family":"Cifuentes-Pagano","sequence":"additional","affiliation":[{"name":"Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute (L.O., E.J., A.D., E.C.-P., P.J.P., P.D.), University of Pittsburgh, PA."},{"name":"Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, PA (E.C.-P., P.J.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7475-808X","authenticated-orcid":true,"given":"Patrick J.","family":"Pagano","sequence":"additional","affiliation":[{"name":"Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute (L.O., E.J., A.D., E.C.-P., P.J.P., P.D.), University of Pittsburgh, PA."},{"name":"Health Sciences Library System (S.C., P.J.P.), University of Pittsburgh, PA."},{"name":"Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, PA (E.C.-P., P.J.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srilakshmi","family":"Chaparala","sequence":"additional","affiliation":[{"name":"Health Sciences Library System (S.C., P.J.P.), University of Pittsburgh, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik S.","family":"Stroes","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, the Netherlands (K.H.Z., L.S., E.S.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7456-1757","authenticated-orcid":true,"given":"Partha","family":"Dutta","sequence":"additional","affiliation":[{"name":"Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute (L.O., E.J., A.D., E.C.-P., P.J.P., P.D.), University of Pittsburgh, PA."},{"name":"Department of Bioengineering, Swanson School of Engineering (L.O., P.D.), University of Pittsburgh, PA."},{"name":"Division of Cardiology, Department of Medicine (P.D.), University of Pittsburgh, PA."},{"name":"Department of Immunology (P.D.), University of Pittsburgh, PA."},{"name":"Pittsburgh VA Medical Center-University Drive, PA (P.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000757"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199202063260605"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000471"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)61249-0"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.286.11.1317"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.593442"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehl441"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.918417"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.2004.025452"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0037-1615367"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1191\/1358863x05vm582oa"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11260"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmg.2019.04.014"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.5694\/j.1326-5377.2004.tb06206.x"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1991.260.6.H1852"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1072-7515(03)00134-0"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.107.160630"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.99.24.3188"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10783"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature17624"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12612"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20110994"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2825"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12984"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2969"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0103-9"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.046038"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aag1381"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1701719"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.114.304652"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12219"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.3791\/1035"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.112.253823"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01068"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/19546"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20041535"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.01.025"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(00)80453-5"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.061986"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.05.004"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1111\/imcb.12035"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2008.08.016"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0307106101"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41421-018-0014-5"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2017-03065"},{"key":"e_1_3_3_47_2","first-page":"163","article-title":"The function of cathepsins B, D, and X in atherosclerosis.","volume":"6","author":"Zhao CF","year":"2016","unstructured":"Zhao, CF, Herrington, DM. The function of cathepsins B, D, and X in atherosclerosis. Am J Cardiovasc Dis. 2016;6:163\u2013170.","journal-title":"Am J Cardiovasc Dis"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.4.1680-1690.2004"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E13-09-0558"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0906761106"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M101031200"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.2291"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.2337\/db09-0949"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00758.2002"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3158-09.2009"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23024"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-05-716480"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-03-0881"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-06-364976"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20050075"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-1566"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.120.315895"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-018-0065-8"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09135"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2010.12.003"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2005.03.007"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000106161.43954.DF"},{"key":"e_1_3_3_68_2","first-page":"7","article-title":"The relationship between the spleen colony-forming cell and the haemopoietic stem cell.","volume":"4","author":"Schofield R","year":"1978","unstructured":"Schofield, R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells. 1978;4:7\u201325.","journal-title":"Blood Cells"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.06.019"},{"key":"e_1_3_3_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0306-4522(02)00165-3"},{"key":"e_1_3_3_71_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2691"},{"key":"e_1_3_3_72_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa4268"},{"key":"e_1_3_3_73_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI57559"},{"key":"e_1_3_3_74_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.113.303097"},{"key":"e_1_3_3_75_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1707914"},{"key":"e_1_3_3_76_2","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.28444"},{"key":"e_1_3_3_77_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.309194"},{"key":"e_1_3_3_78_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.11.025"},{"key":"e_1_3_3_79_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvz107"},{"key":"e_1_3_3_80_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.121.317197"},{"key":"e_1_3_3_81_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.046464"},{"key":"e_1_3_3_82_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.120.314216"},{"key":"e_1_3_3_83_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00953-2"}],"container-title":["Arteriosclerosis, Thrombosis, and Vascular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/ATVBAHA.123.318956","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,12]],"date-time":"2024-05-12T23:31:12Z","timestamp":1715556672000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/ATVBAHA.123.318956"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6]]},"references-count":82,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2023,6]]}},"alternative-id":["10.1161\/ATVBAHA.123.318956"],"URL":"https:\/\/doi.org\/10.1161\/atvbaha.123.318956","relation":{},"ISSN":["1079-5642","1524-4636"],"issn-type":[{"value":"1079-5642","type":"print"},{"value":"1524-4636","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6]]},"assertion":[{"value":"2022-06-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-02-20","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-03-09","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}