{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T09:38:07Z","timestamp":1787564287062,"version":"build-2736575974"},"reference-count":84,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2024,5,10]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>The resiliency of embryonic development to genetic and environmental perturbations has been long appreciated; however, little is known about the mechanisms underlying the robustness of developmental processes. Aberrations resulting in neonatal lethality are exemplified by congenital heart disease arising from defective morphogenesis of pharyngeal arch arteries (PAAs) and their derivatives.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>Mouse genetics, lineage tracing, confocal microscopy, and quantitative image analyses were used to investigate mechanisms of PAA formation and repair.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      The second heart field (SHF) gives rise to the PAA endothelium. Here, we show that the number of SHF-derived endothelial cells (ECs) is regulated by\n                      <jats:italic toggle=\"yes\">VEGFR2<\/jats:italic>\n                      (vascular endothelial growth factor receptor 2) and\n                      <jats:italic toggle=\"yes\">Tbx1<\/jats:italic>\n                      . Remarkably, when the SHF-derived EC number is decreased, PAA development can be rescued by the compensatory endothelium. Blocking such compensatory response leads to embryonic demise. To determine the source of compensating ECs and mechanisms regulating their recruitment, we investigated 3-dimensional EC connectivity, EC fate, and gene expression. Our studies demonstrate that the expression of VEGFR2 by the SHF is required for the differentiation of SHF-derived cells into PAA ECs. The deletion of 1 VEGFR2 allele (\n                      <jats:italic toggle=\"yes\">\n                        VEGFR2\n                        <jats:sup>SHF-HET<\/jats:sup>\n                      <\/jats:italic>\n                      ) reduces SHF contribution to the PAA endothelium, while the deletion of both alleles (\n                      <jats:italic toggle=\"yes\">\n                        VEGFR2\n                        <jats:sup>SHF-KO<\/jats:sup>\n                      <\/jats:italic>\n                      ) abolishes it. The decrease in SHF-derived ECs in\n                      <jats:italic toggle=\"yes\">\n                        VEGFR2\n                        <jats:sup>SHF-HET<\/jats:sup>\n                      <\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">\n                        VEGFR2\n                        <jats:sup>SHF-KO<\/jats:sup>\n                      <\/jats:italic>\n                      embryos is complemented by the recruitment of ECs from the nearby veins. Compensatory ECs contribute to PAA derivatives, giving rise to the endothelium of the aortic arch and the ductus in\n                      <jats:italic toggle=\"yes\">\n                        VEGFR2\n                        <jats:sup>SHF-KO<\/jats:sup>\n                      <\/jats:italic>\n                      mutants. Blocking the compensatory response in\n                      <jats:italic toggle=\"yes\">\n                        VEGFR2\n                        <jats:sup>SHF-KO<\/jats:sup>\n                      <\/jats:italic>\n                      mutants results in embryonic lethality shortly after mid-gestation. The compensatory ECs are absent in\n                      <jats:italic toggle=\"yes\">Tbx1<\/jats:italic>\n                      <jats:sup>+\/-<\/jats:sup>\n                      embryos, a model for 22q11 deletion syndrome, leading to unpredictable arch artery morphogenesis and congenital heart disease.\n                      <jats:italic toggle=\"yes\">Tbx1<\/jats:italic>\n                      regulates the recruitment of the compensatory endothelium in an SHF-non-cell-autonomous manner.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Our studies uncover a novel buffering mechanism underlying the resiliency of PAA development and remodeling.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.123.322767","type":"journal-article","created":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T05:00:46Z","timestamp":1713157246000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["Buffering Mechanism in Aortic Arch Artery Formation and Congenital Heart Disease"],"prefix":"10.1161","volume":"134","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0533-6473","authenticated-orcid":true,"given":"AnnJosette","family":"Ramirez","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Molecular Medicine (A.R., C.A.V., H.Z., S.A.), New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark."},{"name":"Multidisciplinary Ph.D. Program in Biomedical Sciences: Cell Biology, Neuroscience and Physiology Track (A.R., C.A.V., S.A.), New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina A.","family":"Vyzas","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Medicine (A.R., C.A.V., H.Z., S.A.), New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark."},{"name":"Multidisciplinary Ph.D. Program in Biomedical Sciences: Cell Biology, Neuroscience and Physiology Track (A.R., C.A.V., S.A.), New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7931-4330","authenticated-orcid":true,"given":"Huaning","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Medicine (A.R., C.A.V., H.Z., S.A.), New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Eng","sequence":"additional","affiliation":[{"name":"Department of Statistics, School of Arts and Sciences, Rutgers University, Piscataway, NJ (K.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8613-0962","authenticated-orcid":true,"given":"Karl","family":"Degenhardt","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Pennsylvania, Department of Pediatrics, Division of Cardiology, University of Pennsylvania, Philadelphia (K.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9338-9083","authenticated-orcid":true,"given":"Sophie","family":"Astrof","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Medicine (A.R., C.A.V., H.Z., S.A.), New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark."},{"name":"Multidisciplinary Ph.D. Program in Biomedical Sciences: Cell Biology, Neuroscience and Physiology Track (A.R., C.A.V., S.A.), New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2003.09.024"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI38922"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2005.06.004"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000558"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000001052"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.10980"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2016.12.010"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.120.318200"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2015.06.076"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2862"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2011.10.018"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-2007-980040"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-8703(59)90157-7"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1442-2050.2007.00787.x"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.174862"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2005.05.003"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0b013e3182060469"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2015.71"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2010.01.333"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1136\/hrt.58.3.274"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.30.10.807"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9149(86)90256-0"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(76)81049-9"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/85845"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(01)00247-1"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/35065105"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2015.09.016"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.892900"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.3791\/60797"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2006.12.004"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(03)14632-6"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.112.270223"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02086"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.177618"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.205732"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.113639"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.01.021"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.08.014"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2023.04.003"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/376062a0"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(00)80283-4"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1502497112"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2016.07.005"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2017.08.008"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2014.09.014"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.049551"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.061192"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1242\/bio.20148078"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1063889"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1064344"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature17040"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08873"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0288-7"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-022-00615-z"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6758"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.121.054071"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.053047"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.123.323956"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.059881"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3574"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.058776"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.199676"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.201030"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/s1534-5807(03)00363-0"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.227405"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2006.12.048"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.03848"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2005.08.041"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02539"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-05-1970"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2009.01.006"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.02.022"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.1002\/dvg.20335"},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.08.035"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110881"},{"key":"e_1_3_2_77_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mod.2007.05.004"},{"key":"e_1_3_2_78_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-02460-2"},{"key":"e_1_3_2_79_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26966-6"},{"key":"e_1_3_2_80_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"e_1_3_2_81_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202001064"},{"key":"e_1_3_2_82_2","doi-asserted-by":"publisher","DOI":"10.1177\/00220345450240030501"},{"key":"e_1_3_2_83_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCIMAGING.109.918482"},{"key":"e_1_3_2_84_2","first-page":"69","volume-title":"Categorical Data Analysis","author":"Agresti A","year":"2013","unstructured":"Agresti, A. Categorical Data Analysis. 3rd edition, Chapter 3. Wiley-Blackwell; 2013:69\u2013100.","edition":"3"},{"key":"e_1_3_2_85_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02264"}],"container-title":["Circulation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCRESAHA.123.322767","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T17:55:59Z","timestamp":1760982959000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCRESAHA.123.322767"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,10]]},"references-count":84,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2024,5,10]]}},"alternative-id":["10.1161\/CIRCRESAHA.123.322767"],"URL":"https:\/\/doi.org\/10.1161\/circresaha.123.322767","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.03.02.530833","asserted-by":"object"}]},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,10]]},"assertion":[{"value":"2023-03-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-03-20","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-03-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-04-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}