PT  - JOURNAL ARTICLE
AU  - Giulia L.M. Boezio
AU  - Anabela Bensimon-Brito
AU  - Janett Piesker
AU  - Stefan Guenther
AU  - Christian S.M. Helker
AU  - Didier Y.R. Stainier
TI  - Endothelial TGF-β signaling instructs smooth muscle development in the cardiac outflow tract
AID  - 10.1101/2020.01.30.925412
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.01.30.925412
4099  - http://biorxiv.org/content/early/2020/01/31/2020.01.30.925412.short
4100  - http://biorxiv.org/content/early/2020/01/31/2020.01.30.925412.full
AB  - 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-β signaling. To further investigate the role of TGF-β signaling in OFT formation, we generated zebrafish lacking the type I TGF-β 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-β target, partially restores OFT morphology and function. These findings reveal a new requirement for endothelial TGF-β signaling in OFT morphogenesis and suggest an important role for the endothelium in the etiology of aortic malformations.