{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T01:08:34Z","timestamp":1782781714326,"version":"3.54.5"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"16","license":[{"start":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T00:00:00Z","timestamp":1725926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["G091018N"],"award-info":[{"award-number":["G091018N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["G0B5920N"],"award-info":[{"award-number":["G0B5920N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["1107721N"],"award-info":[{"award-number":["1107721N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004040","name":"KU Leuven","doi-asserted-by":"publisher","award":["C14\/19\/095"],"award-info":[{"award-number":["C14\/19\/095"]}],"id":[{"id":"10.13039\/501100004040","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,12,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>During embryonic development, arteriovenous (AV) differentiation ensures proper blood vessel formation and maturation. Defects in arterial or venous identity cause inappropriate fusion of vessels, resulting in atypical shunts, so-called AV malformations (AVMs). Currently, the mechanism behind AVM formation remains unclear, and treatment options are fairly limited. Mammalian AV differentiation is initiated before the onset of blood flow in the embryo; however, this pre-flow mechanism is poorly understood. Here, we aimed to unravel the role of Smad1\/5 signalling in pre-flow arterial identity and, in the process, uncovered an unexpected control mechanism of Smad1\/5 signalling.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>We establish that despite Notch1 being expressed in the pre-flow mouse embryo, it is not activated, nor is it necessary for the expression of the earliest arterial genes in the dorsal aortae (i.e. Hey1 and Gja4). Furthermore, interrupting blood flow by using the Ncx1 KO model completely prevents the activation of Notch1 signalling, suggesting a strong role of shear stress in maintaining arterial identity. We demonstrate that early expression of Hey1 and Gja4 requires SMAD1\/5 signalling. Using embryo cultures, we show that Smad1\/5 signalling is activated through the Alk1\/Alk5\/transforming growth factor (TGF)\u03b2R2 receptor complex, with TGF\u03b21 as a necessary ligand. Furthermore, our findings demonstrate that early arterial gene expression requires the acetylation of Smad1\/5 proteins, rendering them more sensitive to TGF\u03b21 stimulation. Blocking acetyl-CoA production prevents pre-flow arterial expression of Hey1 and Gja4, while stabilizing acetylation rescues their expression.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Our findings highlight the importance of the acetyl-CoA production in the cell and provide a novel control mechanism of Smad1\/5 signalling involving protein acetylation. As disturbed canonical Smad1\/5 signalling is involved in several vascular conditions, our results offer new insights in treatment options for circumventing canonical Smad1\/5 signalling.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvae201","type":"journal-article","created":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T12:33:06Z","timestamp":1725971586000},"page":"2078-2091","source":"Crossref","is-referenced-by-count":6,"title":["Smad1\/5 is acetylated in the dorsal aortae of the mouse embryo before the onset of blood flow, driving early arterial gene expression"],"prefix":"10.1093","volume":"120","author":[{"given":"Margo","family":"Daems","sequence":"first","affiliation":[{"name":"Centre for Molecular and Vascular Biology, KU Leuven , Herestraat 49, bus 911, 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ljuba C","family":"Ponomarev","sequence":"additional","affiliation":[{"name":"Centre for Molecular and Vascular Biology, KU Leuven , Herestraat 49, bus 911, 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Simoes-Faria","sequence":"additional","affiliation":[{"name":"Metabolomics Expertise Centre, VIB Centre for Cancer Biology , 3000 Leuven ,","place":["Belgium"]},{"name":"Department of Cellular and Molecular Medicine, Laboratory of Applied Mass Spectrometry, KU Leuven , 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Nobis","sequence":"additional","affiliation":[{"name":"Intravital Imaging Expertise Centre, VIB Centre for Cancer Biology, KU Leuven , 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colinda L G J","family":"Scheele","sequence":"additional","affiliation":[{"name":"Department of Oncology, Laboratory for Intravital Imaging and Dynamics of Tumour Progression, VIB Centre for Cancer Biology, KU Leuven , 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aernout","family":"Luttun","sequence":"additional","affiliation":[{"name":"Centre for Molecular and Vascular Biology, KU Leuven , Herestraat 49, bus 911, 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart","family":"Ghesqui\u00e8re","sequence":"additional","affiliation":[{"name":"Metabolomics Expertise Centre, VIB Centre for Cancer Biology , 3000 Leuven ,","place":["Belgium"]},{"name":"Department of Cellular and Molecular Medicine, Laboratory of Applied Mass Spectrometry, KU Leuven , 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8583-1721","authenticated-orcid":false,"given":"An","family":"Zwijsen","sequence":"additional","affiliation":[{"name":"Centre for Molecular and Vascular Biology, KU Leuven , Herestraat 49, bus 911, 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2006-7064","authenticated-orcid":false,"given":"Elizabeth A V","family":"Jones","sequence":"additional","affiliation":[{"name":"Centre for Molecular and Vascular Biology, KU Leuven , Herestraat 49, bus 911, 3000 Leuven ,","place":["Belgium"]},{"name":"Department of Cardiology, Maastricht University, CARIM School for Cardiovascular Diseases , Universiteitssingel 50, 6229 ER Maastricht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,9,10]]},"reference":[{"key":"2024121420421443300_cvae201-B1","doi-asserted-by":"crossref","first-page":"2474","DOI":"10.1101\/gad.1239004","article-title":"Dosage-sensitive requirement for mouse Dll4 in artery development","volume":"18","author":"Duarte","year":"2004","journal-title":"Genes 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