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Journal Article

Endothelial TGF-beta signaling instructs smooth muscle cell development in the cardiac outflow tract

MPS-Authors
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Boezio,  Giulia L. M.
Developmental Genetics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Bensimon-Brito,  Anabela
Developmental Genetics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Piesker,  Janett
Electron Microscopy, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Guenther,  Stefan
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Helker,  Christian S. M.
Developmental Genetics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Stainier,  Didier Y. R.
Developmental Genetics, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Citation

Boezio, G. L. M., Bensimon-Brito, A., Piesker, J., Guenther, S., Helker, C. S. M., & Stainier, D. Y. R. (2020). Endothelial TGF-beta signaling instructs smooth muscle cell development in the cardiac outflow tract. ELIFE, 9: e57603. doi:10.7554/eLife.57603.


Cite as: https://hdl.handle.net/21.11116/0000-0007-4E9B-4
Abstract
The development of the cardiac outflow tract (OFT), which connects the heart to the great arteries, relies on a complex crosstalk between endothelial (ECs) and smooth muscle (SMCs) cells. Defects in OFT development can lead to severe malformations, including aortic aneurysms, which are frequently associated with impaired TGF-beta signaling. To better understand the role of TGF-beta signaling in OFT formation, we generated zebrafish lacking the TGF-beta receptor Alk5 and found a strikingly specific dilation of the OFT: alk5-/- OFTs exhibit increased EC numbers as well as extracellular matrix (ECM) and SMC disorganization. Surprisingly, endothelial-specific alk5 overexpression in alk5-/- rescues the EC, ECM, and SMC defects. Transcriptomic analyses reveal downregulation of the ECM gene fibulin-5, which when overexpressed in ECs ameliorates OFT morphology and function. These findings reveal a new requirement for endothelial TGF-beta signaling in OFT morphogenesis and suggest an important role for the endothelium in the etiology of aortic malformations.