{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T01:52:12Z","timestamp":1784339532012,"version":"3.55.0"},"reference-count":67,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2017,11]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">Congenital heart defects are the most common birth defects worldwide. Although defective Notch signaling is the major cause of mouse embryonic death from cardiovascular defects, how Notch signaling is regulated during embryonic vasculogenesis and heart development is poorly understood.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Regulator of G protein signaling 6 (RGS6)\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              \/Ca\n              <jats:sup>2+<\/jats:sup>\n              \/calmodulin\u2010dependent protein kinase II (CaMKII)\n              <jats:sup>VV<\/jats:sup>\n              double mutant mice were developed by crossing\n              <jats:styled-content style=\"fixed-case\">RGS<\/jats:styled-content>\n              6\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice with mice expressing an oxidation\u2010resistant Ca\n              <jats:styled-content style=\"fixed-case\">MKII<\/jats:styled-content>\n              \u03b4 (Ca\n              <jats:styled-content style=\"fixed-case\">\n                MKII\n                <jats:sup>VV<\/jats:sup>\n              <\/jats:styled-content>\n              ), and the resulting embryonic defects\/lethality were investigated using E7.5 to E15.5 embryos. While loss of either\n              <jats:styled-content style=\"fixed-case\">RGS<\/jats:styled-content>\n              6 or oxidized Ca\n              <jats:styled-content style=\"fixed-case\">MKII<\/jats:styled-content>\n              \u03b4 does not alter embryogenesis, their combined loss causes defective Notch signaling, severe cardiovascular defects, and embryonic lethality (\u2248E10.5\u201311.5). Embryos lacking\n              <jats:styled-content style=\"fixed-case\">RGS<\/jats:styled-content>\n              6 and expressing oxidation\u2010resistant Ca\n              <jats:styled-content style=\"fixed-case\">MKII<\/jats:styled-content>\n              \u03b4 exhibit reduced myocardial wall thickness, abnormal trabeculation, and arterial specification defects. Double mutants show vascular remodeling defects, including reduced neurovascularization, delayed neural tube maturation, and small dorsal aortae. These striking cardiovascular defects were accompanied by placental and yolk sac defects in angiogenesis, hematopoiesis, and vascular remodeling similar to what is seen with defective Notch1 signaling. Double mutant hearts, embryos, and yolk sacs exhibit profound downregulation of Notch1, Jagged 1, and Notch downstream target genes Hey1, Hey2, and Hey1L as well as impaired Notch1 signaling in embryos\/hearts.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              <jats:styled-content style=\"fixed-case\">RGS<\/jats:styled-content>\n              6 and oxidized Ca\n              <jats:styled-content style=\"fixed-case\">MKII<\/jats:styled-content>\n              \u03b4 together function as novel critical upstream modulators of Notch signaling required for normal cardiovascular development and embryo survival. Their combined need indicates that they function in parallel pathways needed for Notch1 signaling in yolk sac, placenta and embryos. Thus, dysregulated embryonic\n              <jats:styled-content style=\"fixed-case\">RGS<\/jats:styled-content>\n              6 expression and oxidative activation of Ca\n              <jats:styled-content style=\"fixed-case\">MKII<\/jats:styled-content>\n              may potentially contribute to congenital heart defects.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.117.007038","type":"journal-article","created":{"date-parts":[[2017,10,28]],"date-time":"2017-10-28T00:10:32Z","timestamp":1509149432000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["Essentiality of Regulator of G Protein Signaling 6 and Oxidized Ca\n            <sup>2+<\/sup>\n            \/Calmodulin\u2010Dependent Protein Kinase II in Notch Signaling and\u00a0Cardiovascular Development"],"prefix":"10.1161","volume":"6","author":[{"given":"Bandana","family":"Chakravarti","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianqi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katelin E.","family":"Ahlers\u2010Dannen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zili","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather 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