title: Oscillatory Flow Modulates Mechanosensitive klf2a Expression through trpv4 and trpp2 during Heart Valve Development.
abstract: In vertebrates, heart pumping is required for cardiac morphogenesis and altering myocardial contractility leads to abnormal intracardiac flow forces and valve defects. Among the different mechanical cues generated in the developing heart, oscillatory flow has been proposed to be an essential factor in instructing endocardial cell fate toward valvulogenesis and leads to the expression of klf2a, a known atheroprotective transcription factor. To date, the mechanism by which flow forces are sensed by endocardial cells is not well understood. At the onset of valve formation, oscillatory flows alter the spectrum of the generated wall shear stress (WSS), a key mechanical input sensed by endothelial cells. Here, we establish that mechanosensitive channels are activated in response to oscillatory flow and directly affect valvulogenesis by modulating the endocardial cell response. By combining live imaging and mathematical modeling, we quantify the oscillatory content of the WSS during valve development and demonstrate it sets the endocardial cell response to flow. Furthermore, we show that an endocardial calcium response and the flow-responsive klf2a promoter are modulated by the oscillatory flow through Trpv4, a mechanosensitive ion channel specifically expressed in the endocardium during heart valve development. We made similar observations for Trpp2, a known Trpv4 partner, and show that both the absence of Trpv4 or Trpp2 leads to valve defects. This work identifies a major mechanotransduction pathway involved during valve formation in vertebrates.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Heckel
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France.
authors.forename: Francesco
authors.initials: F
authors.lastname: Boselli
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Roth
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 70, 4056 Basel, Switzerland.
authors.forename: Alice
authors.initials: A
authors.lastname: Krudewig
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 70, 4056 Basel, Switzerland.
authors.forename: Heinz-Georg
authors.initials: HG
authors.lastname: Belting
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Charvin
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France; INSERM, U964, 67404 Illkirch, France; Université de Strasbourg, 67404 Illkirch, France. Electronic address: julien@igbmc.fr.
authors.forename: Julien
authors.initials: J
authors.lastname: Vermot
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001783:Blood Flow Velocity; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D004625:Embryo, Nonmammalian; D004699:Endocardium / Q000196:embryology / Q000502:physiology; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006351:Heart Valves / Q000196:embryology* / Q000502:physiology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008955:Models, Cardiovascular; D008962:Models, Theoretical; D050396:TRPP Cation Channels; D050916:TRPV Cation Channels / Q000235:genetics* / Q000378:metabolism; D020107:Troponin T / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D050982:GATA1 Transcription Factor; C436494:Klf2a protein, zebrafish; D051741:Kruppel-Like Transcription Factors; C547527:PKD2 protein, zebrafish; D050396:TRPP Cation Channels; D050916:TRPV Cation Channels; C571237:TRPV4 protein, zebrafish; D020107:Troponin T; D029961:Zebrafish Proteins; C494691:gata1a protein, zebrafish; C480681:tnnt2a protein, zebrafish; D002118:Calcium