Hemodynamic forces play an essential epigenetic role in heart valve development, but how they do so is not known. Here, we show that the shear-responsive transcription factor KLF2 is required in endocardial cells to regulate the mesenchymal cell responses that remodel cardiac cushions to mature valves. Endocardial Klf2 deficiency results in defective valve formation associated with loss of Wnt9b expression and reduced canonical WNT signaling in neighboring mesenchymal cells, a phenotype reproduced by endocardial-specific loss of Wnt9b. Studies in zebrafish embryos reveal that wnt9b expression is similarly restricted to the endocardial cells overlying the developing heart valves and is dependent upon both hemodynamic shear forces and klf2a expression. These studies identify KLF2-WNT9B signaling as a conserved molecular mechanism by which fluid forces sensed by endothelial cells direct the complex cellular process of heart valve development and suggest that congenital valve defects may arise due to subtle defects in this mechanotransduction pathway. How cardiac cushions are remodeled into mature valve leaflets is not well understood. Goddard et al. find that hemodynamic forces drive expression of KLF2 by the cardiac endocardium. Through a cell non-autonomous mechanism, Klf2 regulates the WNT ligand, Wnt9b, which acts on neighboring mesenchymal cells to control cushion remodeling.
Bibliographical noteFunding Information:
The authors thank members of the Kahn lab and the Sarah Millar lab for discussion and insight during the process of this work. These studies were supported by NIH grants R01HL094326 (M.L.K.), T32HL007954 (L.M.G.), and R0111770 and R01116997 (B.Z). J.V. and A.L.D. are supported by the Agence Nationale de la Recherche (ANR) ( ANR-15-CE13-0015-01 ). J.V. is supported by a European Research Council consolidator grant Evalve ( 682938 ), Fondation pour la Recherche Médicale ( DEQ20140329553 ), and grant ANR-10-LABX-0030-INRT , a French State fund managed by the ANR under the frame program Investissements d’Avenir labeled ANR-10-IDEX-0002-02 .
- cardiac cushion
- heart valve development
- hemodynamic force