Early Progression of Abdominal Aortic Aneurysm is Decelerated by Improved Endothelial Barrier Function via ALDH2‐LIN28B‐ELK3 Signaling

Abstract

The involvement of endothelial barrier function in abdominal aortic aneurysm (AAA) and its upstream regulators remains unknown. Single‐cell RNA sequencing shows that disrupted endothelial focal junction is an early (3 days) and persistent (28 days) event during Angiotensin II (Ang II)‐induced AAA progression. Consistently, mRNA sequencing on human aortic dissection tissues confirmed downregulated expression of endothelial barrier‐related genes. Aldehyde dehydrogenase 2 (ALDH2), a negative regulator of AAA, is found to be upregulated in the intimal media of AAA samples, leading to testing its role in early‐stage AAA. ALDH2 knockdown/knockout specifically in endothelial cells (ECs) significantly increases expression of EC barrier markers related to focal adhesion and tight junction, restores endothelial barrier integrity, and suppresses early aortic dilation of AAA (7 and 14 days post‐Ang II). Mechanically, ELK3 acts as an ALDH2 downstream regulator for endothelial barrier function preservation. At the molecular level, ALDH2 directly binds to LIN28B, a regulator of ELK3 mRNA stability, hindering LIN28B binding to ELK3 mRNA, thereby depressing ELK3 expression and impairing endothelial barrier function. Therefore, preserving vascular endothelial barrier integrity via ALDH2‐specific knockdown in ECs holds therapeutic potential in the early management of AAAs.

Nicotine Potentially Alters Endothelial Inflammation and Cell Adhesion via LGALS9

“…Of note, both processes are of utmost interest because they play pivotal roles in the pathophysiology of several atherosclerosis-associated diseases. For instance, AAA formation in this respect is fundamentally based on the surface expression of cellular adhesion proteins, which in turn allow for inflammatory cell transmigration, also called leukocyte trafficking [6,41].…”

Transcriptomic Analysis of Tight Junction Proteins Demonstrates the Aberrant Expression and Function of Zona Occludens 2 (ZO-2) Protein in Stanford Type A Aortic Dissection

“…In spite of their significant effect on the integrity of vascular tone and permeability, there is still only limited evidence available regarding their altered expression profile in the context of Stanford type A TAAD. In fact, to the best of our knowledge there is only one recent study investigating the role of tight junction proteins (TJPs) in abdominal, and not thoracic, aortic dissections [11]. According to this study, there is an important deregulation of certain TJPs in pathologic abdominal aortas, thus affecting the integrity of the endothelial cell barrier [11].…”

“…In fact, to the best of our knowledge there is only one recent study investigating the role of tight junction proteins (TJPs) in abdominal, and not thoracic, aortic dissections [11]. According to this study, there is an important deregulation of certain TJPs in pathologic abdominal aortas, thus affecting the integrity of the endothelial cell barrier [11].…”