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bioRxiv · 10.1101/2020.01.30.925412

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

Boezio, G. L. M.·Bensimon-Brito, A.·Piesker, J.·Guenther, S.·Helker, C. S. M.·Stainier, D. Y. R.
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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 have often been associated with impaired TGF-{beta} signaling. To further investigate the role of TGF-{beta} signaling in OFT formation, we generated zebrafish lacking the type I TGF-{beta} receptor Alk5 and found a strikingly specific dilation of the OFT. alk5 mutants also exhibit increased EC numbers, extracellular matrix (ECM) and SMC disorganization. Surprisingly, endothelial-specific alk5 overexpression in alk5 mutants rescues both endothelial and SMC defects. Furthermore, modulation of the ECM gene fibulin-5, a TGF-{beta} target, partially restores 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.

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Boezio, G. L. M., Bensimon-Brito, A., Piesker, J., Guenther, S., Helker, C. S. M., Stainier, D. Y. R.. 2020-01-31. Endothelial TGF-β signaling instructs smooth muscle development in the cardiac outflow tract. https://doi.org/10.1101/2020.01.30.925412

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