Valvulogenesis: the moving target

Valvulogenesis is an extremely complex process by which a fragile gelatinous matrix is populated and remodelled during embryonic development into thin fibrous leaflets capable of maintaining unidirectional flow over a lifetime. This process occurs during exposure to constantly changing haemodynamic forces, with a success rate of approximately 99%. Defective valvulogenesis results in impaired cardiac function and lifelong complications. This review integrates what is known about the roles of genetics and mechanics in the development of valves and how changes in either result in impaired morphogenesis. It is hoped that appropriate developmental cues and phenotypic endpoints could help engineers and clinicians in their efforts to regenerate living valve alternatives.

[1]  J. Epstein,et al.  Molecular markers of cardiac endocardial cushion development , 2003, Developmental dynamics : an official publication of the American Association of Anatomists.

[2]  P. Kondaiah,et al.  Embryonic gene expression patterns of TGF beta 1, beta 2 and beta 3 suggest different developmental functions in vivo. , 1991, Development.

[3]  K. Chien,et al.  Synergistic Roles of Neuregulin-1 and Insulin-like Growth Factor-I in Activation of the Phosphatidylinositol 3-Kinase Pathway and Cardiac Chamber Morphogenesis* , 1999, The Journal of Biological Chemistry.

[4]  F. Schoen,et al.  NFATc1 Mediates Vascular Endothelial Growth Factor-induced Proliferation of Human Pulmonary Valve Endothelial Cells* , 2003, Journal of Biological Chemistry.

[5]  Robert H. Anderson,et al.  Lineage and Morphogenetic Analysis of the Cardiac Valves , 2004, Circulation research.

[6]  Masatsugu Hori,et al.  Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[7]  R. Markwald,et al.  Expression of smooth muscle alpha‐actin in mesenchymal cells during formation of avian endocardial cushion tissue: A role for transforming growth factor β3 , 1997, Developmental dynamics : an official publication of the American Association of Anatomists.

[8]  K. Lyons,et al.  BMP signaling is required for septation of the outflow tract of the mammalian heart , 2003, Development.

[9]  D. Stainier,et al.  UDP-glucose dehydrogenase required for cardiac valve formation in zebrafish. , 2001, Science.

[10]  E. Wagner,et al.  Mice humanised for the EGF receptor display hypomorphic phenotypes in skin, bone and heart , 2003, Development.

[11]  David Sedmera,et al.  Developmental anatomy of the heart: a tale of mice and man. , 2003, Physiological genomics.

[12]  A. Moorman,et al.  Development of the Building Plan of the Heart , 2004, Annals of the New York Academy of Sciences.

[13]  S. Hokari,et al.  Mechanisms involved in valvuloseptal endocardial cushion formation in early cardiogenesis: Roles of transforming growth factor (TGF)‐β and bone morphogenetic protein (BMP) , 2000, The Anatomical record.

[14]  David C. Lee,et al.  Defective valvulogenesis in HB‐EGF and TACE‐null mice is associated with aberrant BMP signaling , 2003, The EMBO journal.

[15]  Raymond B. Runyan,et al.  Requirement of type III TGF-beta receptor for endocardial cell transformation in the heart. , 1999, Science.

[16]  D. Rice,et al.  Overlapping and differential localization of Bmp-2, Bmp-4, Msx-2 and apoptosis in the endocardial cushion and adjacent tissues of the developing mouse heart , 2001, Cell and Tissue Research.

[17]  H. Moses,et al.  Activin receptor-like kinase 2 and Smad6 regulate epithelial-mesenchymal transformation during cardiac valve formation. , 2005, Developmental biology.

[18]  R. Kim,et al.  Bmp6 and Bmp7 are required for cushion formation and septation in the developing mouse heart. , 2001, Developmental biology.

[19]  S. Kubalak,et al.  Elevated transforming growth factor beta2 enhances apoptosis and contributes to abnormal outflow tract and aortic sac development in retinoic X receptor alpha knockout embryos. , 2002, Development.

[20]  J. Hurlé,et al.  Malformations of the semilunar valves produced in chick embryos by mechanical interference with cardiogenesis , 1983, Anatomy and Embryology.

[21]  M. Kirby.  Role of extracardiac factors in heart development , 1988, Experientia.

[22]  Martin Baiker,et al.  Changes in Shear Stress–Related Gene Expression After Experimentally Altered Venous Return in the Chicken Embryo , 2005, Circulation research.

[23]  M. Kretzschmar,et al.  Opposing BMP and EGF signalling pathways converge on the TGF-β family mediator Smad1 , 1997, Nature.

[24]  D. Bednarik,et al.  Expression and function of periostin‐isoforms in bone , 2004, Journal of cellular biochemistry.

[25]  Linheng Li,et al.  Notch Activation Results in Phenotypic and Functional Changes Consistent With Endothelial-to-Mesenchymal Transformation , 2004, Circulation research.

[26]  J. Icardo,et al.  Atrioventricular valves of the mouse: III. Collagenous skeleton and myotendinous junction , 1995, The Anatomical record.

[27]  T. M. Yelbuz,et al.  Myocardial volume and organization are changed by failure of addition of secondary heart field myocardium to the cardiac outflow tract , 2003, Developmental dynamics : an official publication of the American Association of Anatomists.

[28]  B. Hogan,et al.  Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse. , 1995, Genes & development.

[29]  R. Markwald,et al.  Immunolocalization of chick periostin protein in the developing heart. , 2005, The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology.

[30]  G. Frantz,et al.  ErbB3 is required for normal cerebellar and cardiac development: a comparison with ErbB2-and heregulin-deficient mice. , 1997, Development.

[31]  R. Markwald,et al.  Embryological Development of the Ventricular Inlets. Septation and Atrioventricular Valve Apparatus , 1998 .

[32]  E. Clark,et al.  Developmental changes in the myocardial architecture of the chick , 1997, The Anatomical record.

[33]  B. Toole,et al.  Hyaluronan in morphogenesis , 1997, Seminars in cell & developmental biology.

[34]  E. Clark,et al.  Remodeling of chick embryonic ventricular myoarchitecture under experimentally changed loading conditions , 1999, The Anatomical record.

[35]  A. Nagy,et al.  Embryonic development is disrupted by modest increases in vascular endothelial growth factor gene expression. , 2000, Development.

[36]  J. Rossant,et al.  Multiple developmental roles of VEGF suggested by a LacZ-tagged allele. , 1999, Developmental biology.

[37]  D. Stainier,et al.  Early Myocardial Function Affects Endocardial Cushion Development in Zebrafish , 2004, PLoS biology.

[38]  S. Klewer,et al.  Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme. , 2000, The Journal of clinical investigation.

[39]  H. Lodish,et al.  A novel mechanism for regulating transforming growth factor beta (TGF-beta) signaling. Functional modulation of type III TGF-beta receptor expression through interaction with the PDZ domain protein, GIPC. , 2001, The Journal of biological chemistry.

[40]  C. Zeiss,et al.  A null mutation of Hhex results in abnormal cardiac development, defective vasculogenesis and elevated Vegfa levels , 2004, Development.

[41]  Raymond B. Runyan,et al.  Cell biology of cardiac cushion development. , 2005, International review of cytology.

[42]  Michiko Watanabe,et al.  Sculpting the cardiac outflow tract. , 2003, Birth defects research. Part C, Embryo today : reviews.

[43]  R. Markwald,et al.  The Cspg2 gene, disrupted in the hdf mutant, is required for right cardiac chamber and endocardial cushion formation. , 1998, Developmental biology.

[44]  Roger R Markwald,et al.  Fibroblast growth factor (FGF)-4 can induce proliferation of cardiac cushion mesenchymal cells during early valve leaflet formation. , 2003, Developmental biology.

[45]  Gabriel Acevedo-Bolton,et al.  Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis , 2003, Nature.

[46]  Robert E. Poelmann,et al.  Development of the atrioventricular valve tension apparatus in the human heart , 1998, Anatomy and Embryology.

[47]  D. Gilliland,et al.  Mouse model of Noonan syndrome reveals cell type– and gene dosage–dependent effects of Ptpn11 mutation , 2004, Nature Medicine.

[48]  D. L. Weeks,et al.  TGFbeta2 and TGFbeta3 have separate and sequential activities during epithelial-mesenchymal cell transformation in the embryonic heart. , 1999, Developmental biology.

[49]  B. Toole,et al.  Hyaluronan in morphogenesis. , 2001, Journal of internal medicine.

[50]  L. Allen.  Stem cells. , 2003, The New England journal of medicine.

[51]  R. Markwald,et al.  The outflow tract of the heart is recruited from a novel heart-forming field. , 2001, Developmental biology.

[52]  J. Massagué,et al.  Smad1 Recognition and Activation by the ALK1 Group of Transforming Growth Factor-β Family Receptors* , 1999, The Journal of Biological Chemistry.

[53]  Beerend P Hierck,et al.  Development‐related changes in the expression of shear stress responsive genes KLF‐2, ET‐1, and NOS‐3 in the developing cardiovascular system of chicken embryos , 2004, Developmental dynamics : an official publication of the American Association of Anatomists.

[54]  S. Klewer,et al.  Heart-valve mesenchyme formation is dependent on hyaluronan-augmented activation of ErbB2–ErbB3 receptors , 2002, Nature Medicine.

[55]  R. Thompson,et al.  Morphogenesis of the truncus arteriosus of the chick embryo heart: Movements of autoradiographic tattoos during septation , 1987, The Anatomical record.

[56]  D. Rimm,et al.  PECAM-1 (CD31) functions as a reservoir for and a modulator of tyrosine-phosphorylated beta-catenin. , 1999, Journal of cell science.

[57]  J. Wehland,et al.  IrpA , is highly homologous to monocytogenesPrfA-regulated gene in Listeria Identification and characterization of a novel , 1996 .

[58]  Raymond B. Runyan,et al.  Slug is an essential target of TGFbeta2 signaling in the developing chicken heart. , 2000, Developmental biology.

[59]  I. Graef,et al.  A Field of Myocardial-Endocardial NFAT Signaling Underlies Heart Valve Morphogenesis , 2004, Cell.

[60]  Raymond B. Runyan,et al.  Antibodies to the Type II TGFbeta receptor block cell activation and migration during atrioventricular cushion transformation in the heart. , 1996, Developmental biology.

[61]  B. Paw,et al.  Vascular endothelial growth factor receptor signaling is required for cardiac valve formation in zebrafish , 2006, Developmental dynamics : an official publication of the American Association of Anatomists.

[62]  V. Hamburger,et al.  A series of normal stages in the development of the chick embryo. 1951. , 2012, Developmental dynamics : an official publication of the American Association of Anatomists.

[63]  Viktor Hamburger,et al.  A series of normal stages in the development of the chick embryo , 1992, Journal of morphology.

[64]  E. Sako.  Newer concepts in the surgical treatment of valvular heart disease , 2004, Current cardiology reports.

[65]  M. DeRuiter,et al.  Myocardial heterogeneity in permissiveness for epicardium-derived cells and endothelial precursor cells along the developing heart tube at the onset of coronary vascularization. , 2005, The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology.

[66]  A. Moorman,et al.  Development of the Myocardium of the Atrioventricular Canal and the Vestibular Spine in the Human Heart , 2001, Circulation research.

[67]  M. Gimbrone,et al.  A role for Smad6 in development and homeostasis of the cardiovascular system , 2000, Nature Genetics.

[68]  D. Sánchez-Quintana,et al.  Histochemical and ultrastructural changes in the extracellular matrix of the developing chick semilunar heart valves. , 1991, Acta anatomica.

[69]  Michael S Sacks,et al.  From Stem Cells to Viable Autologous Semilunar Heart Valve , 2005, Circulation.

[70]  R. Markwald,et al.  Identification and detection of the periostin gene in cardiac development. , 2004, The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology.

[71]  L. Sakai,et al.  Elastic extracellular matrix of the embryonic chick heart: An immunohistological study using laser confocal microscopy , 1994, Developmental dynamics : an official publication of the American Association of Anatomists.

[72]  Robert H. Anderson,et al.  Septation and separation within the outflow tract of the developing heart , 2003, Journal of anatomy.

[73]  L. Leong,et al.  Bone morphogenetic protein-4 , 1996 .

[74]  T. Magnuson,et al.  Mice mutant for Egfr and Shp2 have defective cardiac semilunar valvulogenesis , 2000, Nature Genetics.

[75]  A. Moorman,et al.  Myocardialization of the cardiac outflow tract. , 1999, Developmental biology.

[76]  J. Epstein,et al.  Nf1 has an essential role in endothelial cells , 2003, Nature Genetics.

[77]  A. Moorman,et al.  Normal development of the outflow tract in the rat. , 1998, Circulation research.

[78]  Frank McCormick,et al.  Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. , 2004, Genes & development.

[79]  Robert M Nerem,et al.  Valvular endothelial cells and the mechanoregulation of valvular pathology , 2007, Philosophical Transactions of the Royal Society B: Biological Sciences.

[80]  R. Markwald,et al.  Induction of endocardial cushion tissue in the avian heart is regulated, in part, by TGFbeta-3-mediated autocrine signaling. , 1997, Developmental biology.

[81]  Lynda F. Bonewald,et al.  Identification and Characterization of a Novel Protein, Periostin, with Restricted Expression to Periosteum and Periodontal Ligament and Increased Expression by Transforming Growth Factor β , 1999 .

[82]  R. Markwald,et al.  An In Vivo Analysis of Hematopoietic Stem Cell Potential: Hematopoietic Origin of Cardiac Valve Interstitial Cells , 2006, Circulation research.

[83]  F J Schoen,et al.  Functional Living Trileaflet Heart Valves Grown In Vitro , 2000, Circulation.

[84]  G. Boivin,et al.  TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. , 1997, Development.

[85]  H. Baldwin,et al.  Hyaluronate degradation affects ventricular function of the early postlooped embryonic rat heart in situ. , 1994, Circulation research.

[86]  誠 多々野.  Congenital semilunar valvulogenesis defect in mice deficient in phospholipase Cε , 2005 .

[87]  M. Buckingham,et al.  Rotation of the Myocardial Wall of the Outflow Tract Is Implicated in the Normal Positioning of the Great Arteries , 2006, Circulation research.

[88]  J A Epstein,et al.  Neurofibromin modulation of ras activity is required for normal endocardial-mesenchymal transformation in the developing heart. , 1998, Development.

[89]  M. Kirby,et al.  Neural crest cells contribute to normal aorticopulmonary septation. , 1983, Science.

[90]  A. G. Gittenberger-de Groot,et al.  Epicardial Outgrowth Inhibition Leads to Compensatory Mesothelial Outflow Tract Collar and Abnormal Cardiac Septation and Coronary Formation , 2000, Circulation research.

[91]  K. Yutzey,et al.  DSCR1 gene expression is dependent on NFATc1 during cardiac valve formation and colocalizes with anomalous organ development in trisomy 16 mice. , 2004, Developmental biology.

[92]  Wanmin Song,et al.  Degradation of type IV collagen by matrix metalloproteinases is an important step in the epithelial-mesenchymal transformation of the endocardial cushions. , 2000, Developmental biology.

[93]  A. Harris,et al.  Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function. , 2006, Blood.

[94]  Improved regional wall motion 6 months after direct myocardial revascularization (DMR) with the NOGA DMR system. , 2000, Circulation.

[95]  E. Cuppen,et al.  The Wnt/beta-catenin pathway regulates cardiac valve formation. , 2003, Nature.

[96]  S. Rivkees,et al.  Programmed cell death in the developing heart: Regulation by BMP4 and FGF2 , 2000, Developmental dynamics : an official publication of the American Association of Anatomists.

[97]  R. Price,et al.  Three‐dimensional model system of valvulogenesis , 2005, Developmental dynamics : an official publication of the American Association of Anatomists.

[98]  G. Boivin,et al.  TGF β 2 knockout mice have multiple developmental defects that are non-overlapping with other TGF β knockout phenotypes , 1997 .

[99]  M. Sporn,et al.  Transforming growth factor beta. , 1988, Advances in cancer research.

[100]  R. Markwald,et al.  Cardiac endothelial heterogeneity defines valvular development as demonstrated by the diverse expression of JB3, an antigen of the endocardial cushion tissue. , 1994, Developmental biology.

[101]  Catherine L. Guay,et al.  GATA-6 gene enhancer contains nested regulatory modules for primary myocardium and the embedded nascent atrioventricular conduction system. , 2004, The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology.

[102]  M. Shaw,et al.  Activin receptor-like kinase 2 can mediate atrioventricular cushion transformation. , 2000, Developmental biology.

[103]  熊井 まどか.  Loss of connexin45 causes a cushion defect in early cardiogenesis , 2000 .

[104]  A. Moorman,et al.  Atrial development in the human heart: An immunohistochemical study with emphasis on the role of mesenchymal tissues , 2000, The Anatomical record.

[105]  R. Markwald,et al.  Periostin is expressed within the developing teeth at the sites of epithelial–mesenchymal interaction , 2004, Developmental dynamics : an official publication of the American Association of Anatomists.

[106]  M. Goumans,et al.  Balancing the activation state of the endothelium via two distinct TGF‐β type I receptors , 2002, The EMBO journal.

[107]  M. Pisano,et al.  Intracellular dynamics of Smad‐mediated TGFβ signaling , 2003 .

[108]  J. Hurlé,et al.  Maturation of the extracellular material of the semilunar heart values in the mouse. A histochemical analysis of collagen and mucopolysaccharides. , 1981, Anatomy and embryology.

[109]  Robert M Nerem,et al.  Unique Morphology and Focal Adhesion Development of Valvular Endothelial Cells in Static and Fluid Flow Environments , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[110]  Orlando Aristizábal,et al.  Embryonic Heart Failure in NFATc1−/− Mice: Novel Mechanistic Insights From In Utero Ultrasound Biomicroscopy , 2004, Circulation research.

[111]  S. Maeda,et al.  Congenital Semilunar Valvulogenesis Defect in Mice Deficient in Phospholipase Cε , 2005, Molecular and Cellular Biology.

[112]  W G Henderson,et al.  Outcomes 15 years after valve replacement with a mechanical versus a bioprosthetic valve: final report of the Veterans Affairs randomized trial. , 2000, Journal of the American College of Cardiology.

[113]  P. Carmeliet,et al.  A novel role for VEGF in endocardial cushion formation and its potential contribution to congenital heart defects. , 2001, Development.

[114]  T. Sasaki,et al.  Shear stress enhances prostacyclin release from endocardial endothelial cells. , 1999, Life sciences.

[115]  R. Markwald,et al.  Bone morphogenetic protein-2 can mediate myocardial regulation of atrioventricular cushion mesenchymal cell formation in mice. , 2004, Developmental biology.

[116]  R. Markwald,et al.  Migratory behavior of cardiac cushion tissue cells in a collagen-lattice culture system. , 1982, Developmental biology.

[117]  A. Moorman,et al.  Cardiac chamber formation: development, genes, and evolution. , 2003, Physiological reviews.

[118]  A. Moorman,et al.  Formation of the tricuspid valve in the human heart. , 1995, Circulation.

[119]  C. Crofts,et al.  Structure, stress and tissue repair in aortic valve leaflets. , 1988, Cardiovascular Research.

[120]  R. Markwald,et al.  Periostin (an osteoblast-specific factor) is expressed within the embryonic mouse heart during valve formation , 2001, Mechanisms of Development.

[121]  R. Norris,et al.  Normal distribution of melanocytes in the mouse heart. , 2005, The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology.