Hemodynamic Forces Sculpt Developing Heart Valves through a KLF2-WNT9B Paracrine Signaling Axis

Lauren M, Goddard, Anne Laure, Duchemin, Harini, Ramalingan, Bingruo, Wu, Mei, Chen, Sharika, Bamezai, Jisheng, Yang, Li, Li, Michael P., Morley, Tao, Wang, Marielle, Scherrer-Crosbie, David B., Frank, Kurt A., Engleka, Stephen C., Jameson, Edward E., Morrisey, Thomas J., Carroll, Bin, Zhou, Julien, Vermot, Mark L, Kahn

Developmental Cell | 2017

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-respon- sive transcription factor KLF2 is required in endocar- dial 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 canonicalWNTsignaling in neighboring mesenchymal cells, a phenotype reproduced by endocardial-specific loss of Wnt9b. Studies in zebra- fish embryos reveal that wnt9b expression is simi- larly restricted to the endocardial cells overlying the developing heart valves and is dependent upon both hemodynamic shear forces and klf2a expres- sion. 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 sug- gest that congenital valve defects may arise due to subtle defects in thismechanotransduction pathway.