Ethanol Enhances Endothelial Rigidity by Targeting VE-Cadherin—Implications for Acute Aortic Dissection

Abstract

(1) Background: Acute aortic dissection (AAD) is caused by an endothelial entry tear followed by intimomedial delamination of the outer layers of the vessel wall. The established risk factors include hypertension and smoking. Another rising candidate risk factor is excessive alcohol consumption. This experimental study explores the effects of nicotine (Nic), angiotensin II (Ang II), and ethanol (EtOH) on human aortic endothelial cells (hAoEC). (2) Methods: HAoECs were exposed to Nic, Ang II, and EtOH at different dose levels. Cell migration was studied using the scratch assay and live-cell imaging. The metabolic viability and permeability capacity was investigated using the water-soluble tetrazolium (WST)-1 assay and an in vitro vascular permeability assay. Cell adherence was studied by utilizing the hanging drop assay. The transcriptional and protein level changes were analyzed by RT-qPCR, Western blotting and immunohistochemistry for major junctional complexing proteins. (3) Results: We observed reduced metabolic viability following Ang II and EtOH exposure vs. control. Further, cell adherence was enhanced by EtOH exposure prior to trituration and by all risk factors after trituration, which correlated with the increased gene and protein expression of VE-cadherin upon EtOH exposure. The cell migration capacity was reduced upon EtOH exposure vs. controls. (4) Conclusion: Marked functional changes were observed upon exposure to established and potential risk factors for AAD development in hAoECs. Our findings advocate for an enhanced mechanical rigidity in hAoECs in response to the three substances studied, which in turn might increase endothelial rigidity, suggesting a novel mechanism for developing an endothelial entry tear due to reduced deformability in response to increased shear and pulsatile stress.

Nicotine Potentially Alters Endothelial Inflammation and Cell Adhesion via LGALS9

“…Both CTNNB1 and JUP are known to play critical roles in the cell-cell adhesion of ECs by interacting with VEcadherin, which is a junctional complexing protein that mediates the mechanical strength of adherent junctions [50]. The role of VE-cadherin in AD has recently been suggested by our group [17]. Toward a mechanistic understanding of the development of AD, experimental research approaches focusing on elucidating the exact roles of CTNNB1 and/or JUP in endothelial cell adherence, barrier function, and permeability, which may generate valuable results in the future.…”

“…HAoECs (passage 4-10) were treated with 100 nM Nic (Sigma-Aldrich, St. Louis, MO, USA), 100 nM Ang II (Sigma Aldrich, St. Louis, MO, USA), or in a combination of the two (Comb) for 24 h. The chosen concentrations are within the usual range used for in vitro cell culture studies [16][17][18].…”

The Role of Spatial Aortic Arch Architecture in Type B Aortic Dissection

“…Interestingly, aortic stiffness measurements have recently been suggested as an impactful metric for predicting aortic dissection and quantifying dissection risk [ 26 ]. While stiffness-related remodeling mostly affects the medial aortic layer, recent observations also suggest increased rigidity of the endothelium in response to risk factors as a potential contributing factor to TBAD development [ 27 ].…”