Dissecting Abdominal Aortic Aneurysm Is Aggravated by Genetic Inactivation of LIGHT (TNFSF14)

Andrea Herrero-Cervera,Carla Espinós-Estévez,María Aguilar-Ballester,Susana Martín-Vañó,Ángela Vinué,Laura Piqueras,Alida Taberner-Cortés,Sergio Martínez-Hervás,Herminia González-Navarro

doi:10.3390/biomedicines9111518

Abstract

Abdominal aortic aneurysm (AAA), is a complex disorder characterized by vascular vessel wall remodeling. LIGHT (TNFSF14) is a proinflammatory cytokine associated with vascular disease. In the present study, the impact of genetic inactivation of Light was investigated in dissecting AAA induced by angiotensin II (AngII) in the Apolipoprotein E-deficient (Apoe−/−) mice. Studies in aortic human (ah) vascular smooth muscle cells (VSMC) to study potential translation to human pathology were also performed. AngII-treated Apoe−/−Light−/− mice displayed increased abdominal aorta maximum diameter and AAA severity compared with Apoe−/− mice. Notably, reduced smooth muscle α-actin+ area and Acta2 and Col1a1 gene expression were observed in AAA from Apoe−/−Light−/− mice, suggesting a loss of VSMC contractile phenotype compared with controls. Decreased Opn and augmented Sox9 expression, which are associated with detrimental and non-contractile osteochondrogenic VSMC phenotypes, were also seen in AngII-treated Apoe−/−Light−/− mouse AAA. Consistent with a role of LIGHT preserving VSMC contractile characteristics, LIGHT-treatment of ahVSMCs diminished the expression of SOX9 and of the pluripotency marker CKIT. These effects were partly mediated through lymphotoxin β receptor (LTβR) as the silencing of its gene ablated LIGHT effects on ahVSMCs. These studies suggest a protective role of LIGHT through mechanisms that prevent VSMC trans-differentiation in an LTβR-dependent manner.

Highlights

Abdominal aortic aneurysm (AAA) is a complex and multifactorial disease, and a major cause of morbidity and mortality in males older than 65 years of age [1]
Monitoring of blood pressure in angiotensin II (AngII)-treated mice revealed a gradual increase of SBP and diastolic blood pressure (DBP) in both Apoe−/− and Apoe−/− Light−/− mice (Supplementary Figure S1b,c)
Apoe−/− Light−/− mice, SBP was higher at week 1 and 2 (172.6 ± 6,2 and 181.5 ± 9.2 compared with 135.1 ± 7.3 and 146.3 ± 6.3), and DBP at week 2 compared with controls (142.4 ± 9.0 compared with 111.5 ± 5) (Supplementary Figure S1b,c)

Summary

Introduction

Abdominal aortic aneurysm (AAA) is a complex and multifactorial disease, and a major cause of morbidity and mortality in males older than 65 years of age [1]. Aneurysms remain asymptomatic and are detected by abdominal explorations of unrelated causes or when rupture occurs, engaging fatal events. Potential treatments to prevent their rupture include stabilization of the AAA through invasive or endovascular surgery [1]. AAA develops as the luminal diameter of arteries increases [1] and provokes a vascular dilation due to the weakening of the vessel wall. The lesions in AAA are complex and characterized by elastin fragmentation and degeneration, and leukocytes infiltration. During extravascular remodeling, vascular smooth muscle cells (VSMC)

Methods

Results

Conclusion