title: Foramen ovale closure is a process of endothelial-to-mesenchymal transition leading to fibrosis.
abstract: Patent foramen ovale (PFO) is an atrial septal deformity present in around 25% of the general population. PFO is associated with major causes of morbidity, including stroke and migraine. PFO appears to be heritable but genes involved in the closure of foramen ovale have not been identified. The aim of this study is to determine molecular pathways and genes that are responsible to the postnatal closure of the foramen ovale. Using Sprague-Dawley rat hearts as a model we analysed the dynamic histological changes and gene expressions at the foramen ovale region between embryonic day 20 and postnatal day 7. We observed a gradual loss of the endothelial marker PECAM1, an upregulation of the mesenchymal marker vimentin and α-smooth muscle actin, the elevation of the transcription factor Snail, and an increase of fibroblast activation protein (FAP) in the foramen ovale region as well as the deposition of collagen-rich connective tissues at the closed foramen ovale, suggesting endothelial-to-mesenchymal transition (EndMT) occurring during foramen ovale closure which leads to fibrosis. In addition, Notch1 and Notch3 receptors, Notch ligand Jagged1 and Notch effector HRT1 were highly expressed in the endocardium of the foramen ovale region during EndMT. Activation of Notch3 alone in an endothelial cell culture model was able to drive EndMT and transform endothelial cells to mesenchymal phenotype. Our data demonstrate for the first time that FO closure is a process of EndMT-mediated fibrosis, and Notch signalling is an important player participating in this process. Elucidation of the molecular mechanisms of the closure of foramen ovale informs the pathogenesis of PFO and may provide potential options for screening and prevention of PFO related conditions.
authors.affiliation: Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, United Kingdom.
authors.forename: Graeme C
authors.initials: GC
authors.lastname: Elliott
authors.affiliation: Academic Surgery Unit, Education and Research Centre, University Hospital of South Manchester, Manchester, United Kingdom.
authors.forename: Rockesh
authors.initials: R
authors.lastname: Gurtu
authors.affiliation: Academic Surgery Unit, Education and Research Centre, University Hospital of South Manchester, Manchester, United Kingdom.
authors.forename: Charles
authors.initials: C
authors.lastname: McCollum
authors.affiliation: Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, United Kingdom; Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
authors.affiliation: Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, United Kingdom.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
mesh_terms: D000818:Animals; D054087:Atrial Septum / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000096:biosynthesis; D047108:Embryonic Development; D010450:Endopeptidases; D004727:Endothelium / Q000378:metabolism / Q000473:pathology; D054092:Foramen Ovale, Patent / Q000235:genetics* / Q000473:pathology; D018093:Gelatinases / Q000096:biosynthesis; D015870:Gene Expression / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000096:biosynthesis; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D051881:Receptor, Notch1 / Q000096:biosynthesis; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000096:biosynthesis; D012697:Serine Endopeptidases / Q000096:biosynthesis; D000072099:Serrate-Jagged Proteins; D014746:Vimentin / Q000096:biosynthesis; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D002135:Calcium-Binding Proteins; D010450:Endopeptidases; D018093:Gelatinases; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D051881:Receptor, Notch1; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D012697:Serine Endopeptidases; D000072099:Serrate-Jagged Proteins; D014746:Vimentin; D000099167:Fibroblast Activation Protein Alpha; C000606273:JAG1 protein, human; C000606275:Jag1 protein, rat; C497763:Notch1 protein, rat; C498556:Notch3 protein, rat