Exploring signaling pathways in endothelial mechanotransduction

Mechanotransduction, the process by which cells sense and convert mechanical forces from their surroundings, plays a pivotal role in cellular function. For vascular endothelial cells, coping with the continuous and significant shear stress caused by blood flow is essential for the stability of the circulatory system. Dysfunction in this mechanism can lead to various vascular pathologies, including atherosclerosis and aneurysms. Therefore, understanding how endothelial cells form mechanosensory complexes and thereby respond to external forces is crucial.

This thesis aims to study the involvement of the Angiomotin protein family in endothelial mechanotransduction. The Amot protein family, including Angiomotin (Amot), Angiomotin-Like 1 (AmotL1), and Angiomotin-like 2 (AmotL2), shares common structures as well as protein interaction motifs. However, they exhibit significantly different roles in vascular functions. In Paper I, we elucidate how Amot binds to Talin within the integrin adhesome and regulates force transmission between fibronectin and the cytoskeleton in migrating endothelial cells. Additionally, we demonstrate that deletion of Amot impairs both physiological and pathological angiogenesis. In Paper II, AmotL2 isshown to bind VE cadherin through p120 catenin and connect to the nuclear membrane via actin filaments in aortic endothelial cells, thereby transmitting junctional mechanical signals. Depletion of AmotL2 resulted in a pro-inflammatory response and, in severe cases, leads to the spontaneous formation abdominal aortic aneurysms (AAAs) in male adult mice. In Paper III, it is demonstrated that AmotL1 not only binds to N-cadherin but is also associated with focal adhesion proteins. This suggests that AmotL1 functions may extend beyond endothelial cell junctions to include interactions with the extracellular matrix. Additionally, we provide a comprehensive summary of the protein binding profiles of all Amot proteins, as obtained from BioID-MS analysis, thus offering a global perspective on this protein family.

In conclusion, Amot family proteins, despite their involvement in separate cellular processes, share common connections with a set of junction-related proteins. Furthermore, they exhibit unique, specific binding partners, offering mechanistic insights into the distinct activities of individual Amot proteins.

List of scientific papers

I. The Amot/integrin protein complex transmits mechanical forces required for vascular expansion. Yuanyuan Zhang, Yumeng Zhang, Sumako Kameishi, Giuseppina Barutello, Yujuan Zheng, Nicholas P. Tobin, John Nicosia, Katharina Hennig, David Kung Chun Chiu, Martial Balland, Thomas H. Barker, Federica Cavallo, Lars Holmgren#. Cell reports. 2021, 36(8), 109616. #Corresponding authors.
https://doi.org/10.1016/j.celrep.2021.109616

II. The VE-cadherin/AmotL2 mechanosensory pathway suppresses aortic inflammation and the formation of abdominal aortic aneurysms. Yuanyuan Zhang, Yumeng Zhang, Evelyn Hutterer, Sara Hultin, Otto Bergman, Solrun Kolbeinsdottir, Hong Jin, Maria J. Forteza, Daniel F. J. Ketelhuth, Joy Roy, Ulf Hedin, Martin Enge, Ljubica Matic, Per Eriksson & Lars Holmgren#. Nature Cardiovascular Research. 2023, 2, 629–644. #Corresponding authors.
https://doi.org/10.1038/s44161-023-00298-8

III. Mapping of the Angiomotin protein family Adhesome by BioID Analysis. Yumeng Zhang, Lars Holmgren# and Yuanyuan Zhang. #Corresponding authors. [Manuscript]