Circ Res 95(5): 459-470

Heart Valve Development

Vascular Biology Program and Department of Surgery, Children’s Hospital Boston, Harvard Medical School, Boston, Mass

Correspondence to Joyce Bischoff, PhD, Vascular Biology Program, Children’s Hospital Boston, 300 Longwood Ave, Boston, MA 02115. ude.dravrah.snerdlihc@ffohcsib.ecyoj

Abstract

During the past decade, single gene disruption in mice and large-scale mutagenesis screens in zebrafish have elucidated many fundamental genetic pathways that govern early heart patterning and differentiation. Specifically, a number of genes have been revealed serendipitously to play important and selective roles in cardiac valve development. These initially surprising results have now converged on a finite number of signaling pathways that regulate endothelial proliferation and differentiation in developing and postnatal heart valves. This review highlights the roles of the most well-established ligands and signaling pathways, including VEGF, NFATc1, Notch, Wnt/β-catenin, BMP/TGF-β, ErbB, and NF1/Ras. Based on the interactions among and relative timing of these pathways, a signaling network model for heart valve development is proposed.

Keywords: heart development, heart valves, valvular heart disease, NFAT, VEGF, TGF-β

Abstract

Cardiovascular malformations are the most common congenital anomaly, occurring in four to six infants for every 1000 live births.¹ Defects in cardiac valves and associated structures are the most common subtype, accounting for 25% to 30% of all cardiovascular malformations.² A number of congenital valve defects occur as part of well-defined clinical syndromes, including Down syndrome (numerous cardiac cushion defects), LEOPARD syndrome (pulmonic stenosis), chromosome 22 microdeletion syndromes (truncus arteriosus), Holt-Oram, and Noonan syndrome (pulmonic stenosis). In some cases, including Holt-Oram and Noonan syndrome, the genetic defect has now been convincingly identified.³4 In approximately 25% of cases, however, defects in cardiac cushion development occur separate from any defined syndrome or genetic cause.⁵

In adults, valvular heart disease remains a major cause of morbidity and mortality; approximately 82,000 valve replacements are performed each year in the USA.⁶ Possible therapeutic approaches for these adult heart valve diseases include promoting endogenous repair pathways or using autologous progenitor cells for tissue engineered heart valves.⁷ An increased molecular understanding of the processes controlling heart valve development and remodeling will continue to suggest new therapeutic modalities.⁸

This review is divided into three parts. First, an anatomic description of heart valve development provides orientation for the molecular events that occur during formation of the heart valves. Second, the major cell signaling pathways implicated in heart valve development are reviewed, with an emphasis on the key role played by endothelial cell proliferation and differentiation. Third, we suggest a model that integrates these major signaling pathways into a signaling network for control of cardiac cushion formation and remodeling.

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