Interrogation of the contribution of endothelial cells to aortic aneurysmal disease: unraveling the TGF-ß paradox and the role of nitric oxide.

Impaired TGF-ß signaling has been implied in thoracic aortic aneurysm and dissection (TAAD) related disorders such as Loeys-Dietz syndrome. Although pathogenic variants in genes coding for components of the TGF-ß signaling pathway have been identified as causal for these diseases, the precise mechanisms by which these specific variants lead to pathology remain elusive. Since medial degeneration is the main pathological substrate for TAAD, vascular smooth muscle cell (VSMC) dysfunction is often considered as the main culprit, but the role of endothelial cells (ECs) is neglected. Dysregulated endothelial nitric oxide (NO) signaling contributes to aneurysm development, but its link to TGF-ß signaling remains vague. With this project, I will elucidate the TGF-ß paradox and investigate the effect of impaired TGF-ß signaling on NO regulation by in vivo fluorescent light sheet imaging in zebrafish. I will use an innovative EC and VSMC specific fluorescent TGF-ß reporter to study TGF-ß signaling in real time in a zebrafish Tgfb2 knockout line. Next, by using a novel genetically encoded eNO probe (geNOps), I will investigate how impaired TGF-ß signaling affects NO regulation by in vivo imaging. Finally, I will identify therapeutic targets using an RNA sequencing approach on the novel zebrafish models I developed. This will bring us closer to a curative therapy for life-threatening TAAD and pave the way for the identification of prognostic biomarkers of aortic disease severity.

Keywords:ZEBRAFISH

Disciplines:Vascular diseases, Cell signalling, Genetics