Development, Vol 128, Issue 9 1531-1538, Copyright © 2001 by Company of Biologists

JOURNAL ARTICLES

A novel role for VEGF in endocardial cushion formation and its potential contribution to congenital heart defects

Y Dor, TD Camenisch, A Itin, GI Fishman, JA McDonald, P Carmeliet and E Keshet
Department of Molecular Biology, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.

Normal cardiovascular development is exquisitely dependent on the correct dosage of the angiogenic growth factor and vascular morphogen vascular endothelial growth factor (VEGF). However, cardiac expression of VEGF is also robustly augmented during hypoxic insults, potentially mediating the well-established teratogenic effects of hypoxia on heart development. We report that during normal heart morphogenesis VEGF is specifically upregulated in the atrioventricular (AV) field of the heart tube soon after the onset of endocardial cushion formation (i.e. the endocardium-derived structures that build the heart septa and valves). To model hypoxia-dependent induction of VEGF in vivo, we conditionally induced VEGF expression in the myocardium using a tetracycline-regulated transgenic system. Premature induction of myocardial VEGF in E9.5 embryos to levels comparable with those induced by hypoxia prevented formation of endocardial cushions. When added to explanted embryonic AV tissue, VEGF fully inhibited endocardial-to-mesenchymal transformation. Transformation was also abrogated in AV explants subjected to experimental hypoxia but fully restored in the presence of an inhibitory soluble VEGF receptor 1 chimeric protein. Together, these results suggest a novel developmental role for VEGF as a negative regulator of endocardial-to-mesenchymal transformation that underlies the formation of endocardial cushions. Moreover, ischemia-induced VEGF may be the molecular link between hypoxia and congenital defects in heart septation.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				M. D. Combs and K. E. Yutzey VEGF and RANKL Regulation of NFATc1 in Heart Valve Development Circ. Res., September 11, 2009; 105(6): 565 - 574. [Abstract] [Full Text] [PDF]

				M. D. Combs and K. E. Yutzey Heart Valve Development: Regulatory Networks in Development and Disease Circ. Res., August 28, 2009; 105(5): 408 - 421. [Abstract] [Full Text] [PDF]

				S. D. Kumar, S.-K. Yong, S. T. Dheen, B.-H. Bay, and S. S.-W. Tay Cardiac Malformations Are Associated with Altered Expression of Vascular Endothelial Growth Factor and Endothelial Nitric Oxide Synthase Genes in Embryos of Diabetic Mice Experimental Biology and Medicine, November 1, 2008; 233(11): 1421 - 1432. [Abstract] [Full Text] [PDF]

				O. M. Faye-Petersen and T. M. Crombleholme Twin-to-Twin Transfusion Syndrome: Part 2. Infant Anomalies, Clinical Interventions, and Placental Examination NeoReviews, September 1, 2008; 9(9): e380 - e392. [Abstract] [Full Text] [PDF]

				K. Niessen, Y. Fu, L. Chang, P. A. Hoodless, D. McFadden, and A. Karsan Slug is a direct Notch target required for initiation of cardiac cushion cellularization J. Cell Biol., July 28, 2008; 182(2): 315 - 325. [Abstract] [Full Text] [PDF]

				D. Voskas, Y. Babichev, L. S. Ling, J. Alami, Y. Shaked, R. S. Kerbel, B. Ciruna, and D. J. Dumont An eosinophil immune response characterizes the inflammatory skin disease observed in Tie-2 transgenic mice J. Leukoc. Biol., July 1, 2008; 84(1): 59 - 67. [Abstract] [Full Text] [PDF]

				H. Liu and S. A. Fisher Hypoxia-Inducible Transcription Factor-1{alpha} Triggers an Autocrine Survival Pathway During Embryonic Cardiac Outflow Tract Remodeling Circ. Res., June 6, 2008; 102(11): 1331 - 1339. [Abstract] [Full Text] [PDF]

				K. Niessen and A. Karsan Notch Signaling in Cardiac Development Circ. Res., May 23, 2008; 102(10): 1169 - 1181. [Abstract] [Full Text] [PDF]

				A. K. Greene, S. Kim, G. F. Rogers, S. J. Fishman, B. R. Olsen, and J. B. Mulliken Risk of Vascular Anomalies With Down Syndrome Pediatrics, January 1, 2008; 121(1): e135 - e140. [Abstract] [Full Text] [PDF]

				M. O. Bahtiyar, A. T. Dulay, B. P. Weeks, A. H. Friedman, and J. A. Copel Prevalence of Congenital Heart Defects in Monochorionic/Diamniotic Twin Gestations: A Systematic Literature Review J. Ultrasound Med., November 1, 2007; 26(11): 1491 - 1498. [Abstract] [Full Text] [PDF]

				J. T Butcher and R. R Markwald Valvulogenesis: the moving target Phil Trans R Soc B, August 29, 2007; 362(1484): 1489 - 1503. [Abstract] [Full Text] [PDF]

				M. Wagner and M. A. Q. Siddiqui Signal Transduction in Early Heart Development (II): Ventricular Chamber Specification, Trabeculation, and Heart Valve Formation Experimental Biology and Medicine, July 1, 2007; 232(7): 866 - 880. [Abstract] [Full Text] [PDF]

				N. M.S. van den Akker, D. G.M. Molin, P. P.W.M. Peters, S. Maas, L. J. Wisse, R. van Brempt, C. J. van Munsteren, M. M. Bartelings, R. E. Poelmann, P. Carmeliet, et al. Tetralogy of Fallot and Alterations in Vascular Endothelial Growth Factor-A Signaling and Notch Signaling in Mouse Embryos Solely Expressing the VEGF120 Isoform Circ. Res., March 30, 2007; 100(6): 842 - 849. [Abstract] [Full Text] [PDF]

				F.-E Mo and L. F. Lau The Matricellular Protein CCN1 Is Essential for Cardiac Development Circ. Res., October 27, 2006; 99(9): 961 - 969. [Abstract] [Full Text] [PDF]

				S. Paruchuri, J.-H. Yang, E. Aikawa, J. M. Melero-Martin, Z. A. Khan, S. Loukogeorgakis, F. J. Schoen, and J. Bischoff Human Pulmonary Valve Progenitor Cells Exhibit Endothelial/Mesenchymal Plasticity in Response to Vascular Endothelial Growth Factor-A and Transforming Growth Factor-{beta}2 Circ. Res., October 13, 2006; 99(8): 861 - 869. [Abstract] [Full Text] [PDF]

				A. Ouvrard-Pascaud, Y. Sainte-Marie, J.-P. Benitah, R. Perrier, C. Soukaseum, A. N. D. Cat, A. Royer, K. Le Quang, F. Charpentier, S. Demolombe, et al. Conditional Mineralocorticoid Receptor Expression in the Heart Leads to Life-Threatening Arrhythmias Circulation, June 14, 2005; 111(23): 3025 - 3033. [Abstract] [Full Text] [PDF]

				H. Hallaq, E. Pinter, J. Enciso, J. McGrath, C. Zeiss, M. Brueckner, J. Madri, H. C. Jacobs, C. M. Wilson, H. Vasavada, et al. A null mutation of Hhex results in abnormal cardiac development, defective vasculogenesis and elevated Vegfa levels Development, October 15, 2004; 131(20): 5197 - 5209. [Abstract] [Full Text] [PDF]

				E. J. Armstrong and J. Bischoff Heart Valve Development: Endothelial Cell Signaling and Differentiation Circ. Res., September 3, 2004; 95(5): 459 - 470. [Abstract] [Full Text] [PDF]

				S. Liebner, A. Cattelino, R. Gallini, N. Rudini, M. Iurlaro, S. Piccolo, and E. Dejana {beta}-Catenin is required for endothelial-mesenchymal transformation during heart cushion development in the mouse J. Cell Biol., August 2, 2004; 166(3): 359 - 367. [Abstract] [Full Text] [PDF]

				D. Hilfiker-Kleiner, K. Kaminski, A. Kaminska, M. Fuchs, G. Klein, E. Podewski, K. Grote, I. Kiian, K. C. Wollert, A. Hilfiker, et al. Regulation of Proangiogenic Factor CCN1 in Cardiac Muscle: Impact of Ischemia, Pressure Overload, and Neurohumoral Activation Circulation, May 11, 2004; 109(18): 2227 - 2233. [Abstract] [Full Text] [PDF]

				P.-N. Tsao, Y.-N. Su, H. Li, P.-H. Huang, C.-T. Chien, Y.-L. Lai, C.-N. Lee, C.-A. Chen, W.-F. Cheng, S.-C. Wei, et al. Overexpression of Placenta Growth Factor Contributes to the Pathogenesis of Pulmonary Emphysema Am. J. Respir. Crit. Care Med., February 15, 2004; 169(4): 505 - 511. [Abstract] [Full Text] [PDF]

				T. Toyofuku, H. Zhang, A. Kumanogoh, N. Takegahara, F. Suto, J. Kamei, K. Aoki, M. Yabuki, M. Hori, H. Fujisawa, et al. Dual roles of Sema6D in cardiac morphogenesis through region-specific association of its receptor, Plexin-A1, with off-track and vascular endothelial growth factor receptor type 2 Genes & Dev., February 15, 2004; 18(4): 435 - 447. [Abstract] [Full Text] [PDF]

				P. G. Hogan, L. Chen, J. Nardone, and A. Rao Transcriptional regulation by calcium, calcineurin, and NFAT Genes & Dev., September 15, 2003; 17(18): 2205 - 2232. [Full Text] [PDF]

				J. Ou, Z. Ou, D. G. McCarver, R. N. Hines, K. T. Oldham, A. W. Ackerman, and K. A. Pritchard Jr. Trichloroethylene Decreases Heat Shock Protein 90 Interactions with Endothelial Nitric Oxide Synthase: Implications for Endothelial Cell Proliferation Toxicol. Sci., May 1, 2003; 73(1): 90 - 97. [Abstract] [Full Text] [PDF]

				A. Sanbe, J. Gulick, M. C. Hanks, Q. Liang, H. Osinska, and J. Robbins Reengineering Inducible Cardiac-Specific Transgenesis With an Attenuated Myosin Heavy Chain Promoter Circ. Res., April 4, 2003; 92(6): 609 - 616. [Abstract] [Full Text] [PDF]

				J. M. Enciso, D. Gratzinger, T. D. Camenisch, S. Canosa, E. Pinter, and J. A. Madri Elevated glucose inhibits VEGF-A-mediated endocardial cushion formation: modulation by PECAM-1 and MMP-2 J. Cell Biol., February 18, 2003; 160(4): 605 - 615. [Abstract] [Full Text] [PDF]

				E. N. Johnson, Y. M. Lee, T. L. Sander, E. Rabkin, F. J. Schoen, S. Kaushal, and J. Bischoff NFATc1 Mediates Vascular Endothelial Growth Factor-induced Proliferation of Human Pulmonary Valve Endothelial Cells J. Biol. Chem., January 10, 2003; 278(3): 1686 - 1692. [Abstract] [Full Text] [PDF]

				Z. Yin, J. Haynie, X. Yang, B. Han, S. Kiatchoosakun, J. Restivo, S. Yuan, N. R. Prabhakar, K. Herrup, R. A. Conlon, et al. The essential role of Cited2, a negative regulator for HIF-1alpha , in heart development and neurulation PNAS, August 6, 2002; 99(16): 10488 - 10493. [Abstract] [Full Text] [PDF]