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Understanding genes and mechanisms regulating PAA formation will provide important insights into the etiology and treatments for congenital heart disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective:<\/jats:title>\n                    <jats:p>\n                      Cell-ECM (extracellular matrix) interactions play essential roles in the morphogenesis of PAAs and their derivatives, the aortic arch artery and its major branches; however, their specific functions are not well-understood. Previously, we demonstrated that integrin \u03b15\u03b21 and Fn1 (fibronectin) expressed in the\n                      <jats:italic toggle=\"yes\">Isl1<\/jats:italic>\n                      lineages regulate PAA formation. The objective of the current studies was to investigate cellular mechanisms by which integrin \u03b15\u03b21 and Fn1 regulate aortic arch artery morphogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results:<\/jats:title>\n                    <jats:p>\n                      Using temporal lineage tracing, whole-mount confocal imaging, and quantitative analysis of the second heart field (SHF) and endothelial cell (EC) dynamics, we show that the majority of PAA EC progenitors arise by E7.5 in the SHF and contribute to pharyngeal arch endothelium between E7.5 and E9.5. Consequently, SHF-derived ECs in the pharyngeal arches form a plexus of small blood vessels, which remodels into the PAAs by 35 somites. The remodeling of the vascular plexus is orchestrated by signals dependent on the pharyngeal ECM microenvironment, extrinsic to the endothelium. Conditional ablation of integrin \u03b15\u03b21 or Fn1 in the\n                      <jats:italic toggle=\"yes\">Isl1<\/jats:italic>\n                      lineages showed that signaling by the ECM regulates aortic arch artery morphogenesis at multiple steps: (1) accumulation of SHF-derived ECs in the pharyngeal arches, (2) remodeling of the EC plexus in the fourth arches into the PAAs, and (3) differentiation of neural crest-derived cells adjacent to the PAA endothelium into vascular smooth muscle cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>PAA formation is a multistep process entailing dynamic contribution of SHF-derived ECs to pharyngeal arches, the remodeling of endothelial plexus into the PAAs, and the remodeling of the PAAs into the aortic arch artery and its major branches. Cell-ECM interactions regulated by integrin \u03b15\u03b21 and Fn1 play essential roles at each of these developmental stages.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.120.318200","type":"journal-article","created":{"date-parts":[[2020,11,30]],"date-time":"2020-11-30T05:00:17Z","timestamp":1606712417000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":26,"title":["Cell-Extracellular Matrix Interactions Play Multiple Essential Roles in Aortic Arch Development"],"prefix":"10.1161","volume":"128","author":[{"given":"Michael","family":"Warkala","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark (M.W., A.R., M.S., H.Z., S.A.)."},{"name":"Multidisciplinary PhD Program in Biomedical Sciences: Molecular Biology, Genetics, and Cancer Track, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark (M.W., S.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongying","family":"Chen","sequence":"additional","affiliation":[{"name":"Graduate Program in Cell and Developmental Biology, Thomas Jefferson University, Philadelphia, PA (D.C., A.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"AnnJosette","family":"Ramirez","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark (M.W., A.R., M.S., H.Z., S.A.)."},{"name":"Multidisciplinary PhD Program in Biomedical Sciences: Cell Biology, Neuroscience and Physiology Track, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark (A.R., M.S., S.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5757-4270","authenticated-orcid":true,"given":"Ali","family":"Jubran","sequence":"additional","affiliation":[{"name":"Graduate Program in Cell and Developmental Biology, Thomas Jefferson University, Philadelphia, PA (D.C., A.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0624-3332","authenticated-orcid":true,"given":"Michael","family":"Schonning","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark (M.W., A.R., M.S., H.Z., S.A.)."},{"name":"Multidisciplinary PhD Program in Biomedical Sciences: Cell Biology, Neuroscience and Physiology Track, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark (A.R., M.S., S.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Wang","sequence":"additional","affiliation":[],"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, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark (M.W., A.R., M.S., H.Z., S.A.)."}],"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, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark (M.W., A.R., M.S., H.Z., S.A.)."},{"name":"Multidisciplinary PhD Program in Biomedical Sciences: Molecular Biology, Genetics, and Cancer Track, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark (M.W., S.A.)."},{"name":"Multidisciplinary PhD Program in Biomedical Sciences: Cell Biology, Neuroscience and Physiology Track, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark (A.R., M.S., S.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2005.06.004"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/s1010-7940(97)00194-2"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00247-010-1607-9"},{"key":"e_1_3_6_5_2","first-page":"33","article-title":"Subclavian steal syndrome: neurotological manifestations.","volume":"27","author":"Psillas G","year":"2007","unstructured":"Psillas, G, Kekes, G, Constantinidis, J, Triaridis, S, Vital, V. 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