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

eLife

Stefan Guenther¹  Didier YR Stainier²  Christian SM Helker²  Anabela Bensimon-Brito²  Giulia LM Boezio²  Janett Piesker³ 

[1] Bioinformatics and Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany;Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany;Scientific Service Group Microscopy, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany;

关键词: outflow tract;    TGF-β;    Endothelium;    smooth muscle cells;    cellular cross-talk;    extracellular matrix;   

DOI  :  10.7554/eLife.57603

来源: DOAJ

【 摘 要 】

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-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.

【 授权许可】

Unknown