|ZFIN ID: ZDB-PUB-201002-206|
Endothelial TGF-β signaling instructs smooth muscle cell development in the cardiac outflow tract
Boezio, G.L., Bensimon-Brito, A., Piesker, J., Guenther, S., Helker, C.S., Stainier, D.Y.
|Source:||eLIFE 9: (Journal)|
|Registered Authors:||Helker, Christian, Stainier, Didier|
|Keywords:||Endothelium, TGF-β, cellular cross-talk, developmental biology, extracellular matrix, outflow tract, smooth muscle cells, zebrafish|
|PubMed:||32990594 Full text @ Elife|
Boezio, G.L., Bensimon-Brito, A., Piesker, J., Guenther, S., Helker, C.S., Stainier, D.Y. (2020) Endothelial TGF-β signaling instructs smooth muscle cell development in the cardiac outflow tract. eLIFE. 9:.
ABSTRACTThe 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-β signaling. To better understand the role of TGF-β signaling in OFT formation, we generated zebrafish lacking the TGF-β 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-β signaling in OFT morphogenesis and suggest an important role for the endothelium in the etiology of aortic malformations.