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Regulation of heart valve morphogenesis by Eph receptor ligand, ephrin-A1.

http://www.ncbi.nlm.nih.gov/pubmed/20960543

Disease or malformation of heart valves is one of the leading causes of morbidity and mortality in both children and adults. These congenital anomalies can remain undetected until cardiac function is compromised, making it important to understand the underlying nature of these disorders. Here we show that ephrin-A1, a ligand for class A Eph receptor tyrosine kinases, regulates cardiac valve formation. Exogenous ephrin-A1-Fc or overexpression of ephrin-A1 in the heart inhibits epithelial-to-mesenchymal transformation (EMT) in chick atrioventricular cushion explants. In contrast, overexpression of wild-type EphA3 receptor promotes EMT via a kinase-dependent mechanism. To analyze ephrin-A1 in vivo, we generated an ephrin-A1 knockout mouse through gene targeting. Ephrin-A1 null animals are viable but exhibit impaired cardiac function. Loss of ephrin-A1 results in thickened aortic and mitral valves in newborn and adult animals. Analysis of early embryonic hearts revealed increased cellularity in outflow tract endocardial cushions and elevated mesenchymal marker expression, suggesting that excessive numbers of cells undergo EMT. Taken together, these data indicate that ephrin-A1 regulates cardiac valve development, making ephrin-A1-deficient mice a novel model for congenital heart defects.

Pubmed ID: 20960543 RIS Download

Mesh terms: Animals | Echocardiography | Ephrin-A1 | Female | Heart | Heart Valves | Male | Mice | Mice, Knockout | Morphogenesis

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Associated grants

  • Agency: NCI NIH HHS, Id: CA114301
  • Agency: NCI NIH HHS, Id: CA95004
  • Agency: NHLBI NIH HHS, Id: HL0952551
  • Agency: NCI NIH HHS, Id: R01 CA095004
  • Agency: NCI NIH HHS, Id: R01 CA095004-09
  • Agency: NCI NIH HHS, Id: R01 CA114301
  • Agency: NCI NIH HHS, Id: R01 CA114301-05
  • Agency: NHLBI NIH HHS, Id: R01 HL085708
  • Agency: NHLBI NIH HHS, Id: R01 HL085708-03
  • Agency: NIGMS NIH HHS, Id: T32 GM007628
  • Agency: NIGMS NIH HHS, Id: T32 GM007628
  • Agency: NIGMS NIH HHS, Id: T32 GM007628-28
  • Agency: NICHD NIH HHS, Id: T32 HD07390
  • Agency: NHLBI NIH HHS, Id: T32 HL007751
  • Agency: NHLBI NIH HHS, Id: T32 HL007751-14

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