{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:12:05Z","timestamp":1791234725397,"version":"4.1.0"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>A sustained dosage of VEGFA (vascular endothelial growth factor A) is crucial for angiogenesis in both homeostasis and cardiovascular diseases. Start codon CUG-initiated alternative translation is a conserved mechanism for producing mature VEGFA. Genetic surveys have identified stop-gained variants predicted to prematurely terminate CUG-initiated translation without affecting start codon ATG-initiated translation. However, the impacts of these variants on the vasculature in steady-state and disease conditions remain unknown.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              Using CRISPR\/Cas9 genome editing, we established the\n              <jats:italic toggle=\"yes\">Vegfa<\/jats:italic>\n              <jats:sup>\n                <jats:italic toggle=\"yes\">Q150X\/Q150<\/jats:italic>\n              <\/jats:sup>\n              allele (Q150X), a mouse genetic model that mimics the human VEGFA stop-gained variant. The effects of this variant were tested in both adult homeostatic conditions and the acute myocardial infarction (MI) model. We analyzed and quantified cardiac vasculature structure using immunofluorescence and light-sheet imaging. Furthermore, we characterized cellular heterogeneity, cell-cell interactions, and gene regulation using single-nucleus RNA sequencing, as well as cell type-specific transcriptomics and epigenomics.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Homozygous mice carrying the stop-gained variant were viable. VEGFA dosage was reduced to 70% in the Q150X homeostatic heart, with no significant alteration in cardiac function or vasculature. In the MI model, VEGFA dosage in Q150X was reduced to about 40% within the first week post-infarction, leading to functional deterioration in the post-MI hearts. Significant changes in cellular composition were observed 3 days post-MI. In particular, endothelial cells in Q150X diverged into a state that showed a higher level of hypoxia stress, an elevated inflammatory response, and increased extracellular matrix secretion. In addition, we observed an increase in Nppb\n              <jats:sup>+<\/jats:sup>\n              stressed cardiomyocytes in both 3 days post-MI and homeostasis. Finally, proinflammatory macrophages, neutrophils, and Cd8\n              <jats:sup>+<\/jats:sup>\n              T cells were enriched in the ischemic zone of Q150X hearts.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>CUG-initiated translation contributes significantly to the production of mature VEGFA in ischemic hearts. VEGFA dosage is critical in determining the cellular microenvironment during ischemic injury.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.124.004879","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T09:00:10Z","timestamp":1752829210000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["VEGFA Stop-Gained Variant Deteriorates Cardiac Remodeling in Myocardial Infarction"],"prefix":"10.1161","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3821-7569","authenticated-orcid":true,"given":"Zhongxiang","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pediatric Cardiology, Shanghai Children\u2019s Medical Center, Shanghai Jiaotong University School of Medicine, China (Z.C., D.Z., Y.C., Y.H., Z.Y., F.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diqi","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, Shanghai Children\u2019s Medical Center, Shanghai Jiaotong University School of Medicine, China (Z.C., D.Z., Y.C., Y.H., Z.Y., F.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaa Seng","family":"Lai","sequence":"additional","affiliation":[{"name":"Pediatric Translational Medicine Institute and Pediatric Congenital Heart Disease Institute, Shanghai Children\u2019 s Medical Center, Shanghai Jiaotong University School of Medicine, China (K.S.L., Y.F., B.H., Z.Z., M.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, Shanghai Children\u2019s Medical Center, Shanghai Jiaotong University School of Medicine, China (Z.C., D.Z., Y.C., Y.H., Z.Y., F.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8845-7176","authenticated-orcid":true,"given":"Yuqing","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, Shanghai Children\u2019s Medical Center, Shanghai Jiaotong University School of Medicine, China (Z.C., D.Z., Y.C., Y.H., Z.Y., F.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yabo","family":"Fang","sequence":"additional","affiliation":[{"name":"Pediatric Translational Medicine Institute and Pediatric Congenital Heart Disease Institute, Shanghai Children\u2019 s Medical Center, Shanghai Jiaotong University School of Medicine, China (K.S.L., Y.F., B.H., Z.Z., M.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihang","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, Shanghai Children\u2019s Medical Center, Shanghai Jiaotong University School of Medicine, China (Z.C., D.Z., Y.C., Y.H., Z.Y., F.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0335-2258","authenticated-orcid":true,"given":"Beibei","family":"Hu","sequence":"additional","affiliation":[{"name":"Pediatric Translational Medicine Institute and Pediatric Congenital Heart Disease Institute, Shanghai Children\u2019 s Medical Center, Shanghai Jiaotong University School of Medicine, China (K.S.L., Y.F., B.H., Z.Z., M.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9898-054X","authenticated-orcid":true,"given":"Zhen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Pediatric Translational Medicine Institute and Pediatric Congenital Heart Disease Institute, Shanghai Children\u2019 s Medical Center, Shanghai Jiaotong University School of Medicine, China (K.S.L., Y.F., B.H., Z.Z., M.Z.)."},{"name":"Shanghai Collaborative Innovative Centre of Intelligent Medical Device and Active Health, Shanghai University of Medicine and Health Sciences, China (Z.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7055-6790","authenticated-orcid":true,"given":"Min","family":"Zhang","sequence":"additional","affiliation":[{"name":"Pediatric Translational Medicine Institute and Pediatric Congenital Heart Disease Institute, Shanghai Children\u2019 s Medical Center, Shanghai Jiaotong University School of Medicine, China (K.S.L., Y.F., B.H., Z.Z., M.Z.)."},{"name":"Core Research Laboratory, Fujian Children\u2019s Hospital, China (Z.Z.)"},{"name":"Department of Hainan Key Laboratory of Molecular Medicine for Women and Children\u2019 s Health, Shanghai Children\u2019 s Medical Center Hainan Branch, Shanghai Jiao Tong University School of Medicine, Sanya, China (Z.Z.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0162-2595","authenticated-orcid":true,"given":"Fen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, Shanghai Children\u2019s Medical Center, Shanghai Jiaotong University School of Medicine, China (Z.C., D.Z., Y.C., Y.H., Z.Y., F.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.312310"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehz305"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1605431113"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-07524-x"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01233-6"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2010.04.124"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/380435a0"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/380439a0"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2892"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1210\/mend.15.12.0738"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.010"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mvr.2010.03.014"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0735-1097(02)02121-6"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.70246"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature14483"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2023.07.019"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0591-3"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.172161899"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1053\/euhj.2001.2963"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02762-z"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvt228"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.118.314028"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-42690-9"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.303577"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.091415198"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt539"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-022-00047-3"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2020.02.019"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-022-00140-7"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.038944"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.036099"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.06.054"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2009.00811.x"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13127"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41525-023-00386-5"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.3791\/52197-v"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.3233\/ACP-CLO-2010-0548"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2021.101097"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","unstructured":"Cai R Kolabas ZI Pan C Mai H Zhao S Kaltenecker D Voigt FF Molbay M Ohn T-l Vincke C et al. Whole-mouse clearing and imaging at the cellular level with vdisco. Nat Protoc. 2023;18:1197\u20131242. doi: 10.1038\/s41596-022-00788-2","DOI":"10.1038\/s41596-022-00788-2"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.77419"}],"container-title":["Circulation: Genomic and Precision Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCGEN.124.004879","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T18:00:30Z","timestamp":1755626430000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCGEN.124.004879"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8]]},"references-count":41,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1161\/CIRCGEN.124.004879"],"URL":"https:\/\/doi.org\/10.1161\/circgen.124.004879","relation":{},"ISSN":["2574-8300"],"issn-type":[{"value":"2574-8300","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8]]},"assertion":[{"value":"2024-08-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}