RT Journal Article
SR Electronic
T1 The VE-cadherin/AmotL2 mechanosensory pathway suppresses aortic inflammation and the formation of abdominal aortic aneurysms
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.05.07.443138
DO 10.1101/2021.05.07.443138
A1 Yuanyuan Zhang
A1 Evelyn Hutterer
A1 Sara Hultin
A1 Otto Bergman
A1 Maria J. Forteza
A1 Zorana Andonovic
A1 Daniel F.J. Ketelhuth
A1 Joy Roy
A1 Per Eriksson
A1 Lars Holmgren
YR 2021
UL http://biorxiv.org/content/early/2021/05/07/2021.05.07.443138.abstract
AB Arterial endothelial cells (ECs) have the ability to respond to mechanical forces exerted by fluid shear stress. This response is of importance, as it is protective against vascular diseases such as atherosclerosis and aortic aneurysms. Mechanical forces are transmitted at the sites of adhesion to the basal membrane as well as cell-cell junctions where protein complexes connect to the cellular cytoskeleton to relay force into the cell. Here we present a novel protein complex that connects junctional VE-cadherin and radial actin filaments to the LINC complex in the nuclear membrane. We show that the scaffold protein AmotL2 is essential for the formation of radial actin filaments and the flow-induced alignment of aortic and arterial ECs. The deletion of endothelial AmotL2 alters nuclear shape as well as subcellular positioning. Molecular analysis shows that VE-cadherin is mechanically associated with the nuclear membrane via binding to AmotL2 and Actin. Furthermore, the deletion of AmotL2 in ECs provokes a pro-inflammatory response and abdominal aortic aneurysms (AAA) in the aorta of mice on a normal diet. Remarkably, transcriptome analysis of AAA samples from human patients revealed a negative correlation between AmotL2 expression and aneurysm diameters, as well as a positive correlation between AmotL2 and YAP expression. These findings provide a conceptual framework regarding how mechanotransduction in the junctions is coupled with vascular disease.Competing Interest StatementThe authors have declared no competing interest.