Extracellular Tuning of Mitochondrial Respiration Leads to Aortic Aneurysm

Abstract

Background: Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue caused by mutations in the FBN1 gene encoding a large glycoprotein in the extracellular matrix called fibrillin-1. The major complication of this connective disorder is the risk to develop thoracic aortic aneurysm (TAA). To date, no effective pharmacological therapies have been identified for the management of thoracic aortic disease and the only options capable of preventing aneurysm rupture are endovascular repair or open surgery. Here, we have studied the role of mitochondrial dysfunction in the progression of thoracic aortic aneurysm and mitochondrial boosting strategies as a potential treatment to managing aortic aneurysms. Methods: Combining transcriptomics and metabolic analysis of aortas from a Marfan mouse model ( Fbn1 c1039g/+ ) and MFS-patients, we have identified mitochondrial dysfunction alongside with mtDNA depletion as a new hallmark of aortic aneurysm disease in MFS. To demonstrate the importance of mitochondrial decline in the development of aneurysms, we generated a conditional mouse model with mitochondrial dysfunction specifically in vascular smooth muscle cells (VSMCs) by conditional depleting mitochondrial transcription factor A (Tfam) ( Myh11-Cre ERT2 Tfam flox/flox mice). We have used a mouse model of Marfan syndrome to test for drugs that can revert aortic disease by enhancing Tfam levels and mitochondrial respiration Results: The main canonical pathways highlighted in the transcriptomic analysis in aortas from Fbn1 c1039g/+ mice were those related to metabolic function, such as mitochondrial dysfunction. Mitochondrial complexes, whose transcription depends on Tfam and mitochondrial-DNA content, were reduced in aortas from young Fbn1 c1039g/+ mice. In vitro experiments in Fbn1 -silenced VSMCs presented increased lactate production and decreased oxygen consumption. Similar results were found in MFS-patients. VSMCs seeded in matrices produced by Fbn1-deficient VSMCs undergo mitochondrial dysfunction. Conditional Tfam-deficient-VSMCs mice, lose their contractile capacity, showed aortic aneurysms and died prematurely. Restoring mitochondrial metabolism with the NAD precursor nicotinamide riboside (NR) rapidly reverses aortic aneurysm in Fbn1 c1039g/+ mice. Conclusions: Mitochondrial function of VSMCs is controlled by the extracellular matrix and drives the development of aortic aneurysm in Marfan Syndrome. Targeting vascular metabolism is a new available therapeutic strategy for managing aortic aneurysms associated with genetic disorders.

Aorta smooth muscle-on-a-chip reveals impaired mitochondrial dynamics as a therapeutic target for aortic aneurysm in bicuspid aortic valve disease

“…HAoSMCs transform from a contractile into a synthetic phenotype and induce loose of vascular tone, which is one of the major pathological process in TAA. Thus, the enhancement of HAoSMCs contractility is indicative of the effectiveness of pharmacotherapy for controlling aortic aneurysm ( Oller et al, 2021 ). In this study, we found that NOTCH1 insufficiency in HAoSMCs downregulated the contractile phenotype proteins SM22 and CNN1 under rhythmic strain.…”

“…Mitochondrial dysfunction has been closely linked to a variety of cardiovascular disorders, such as heart failure and atherosclerosis. Recent studies found that mitochondrial dysfunction was also related to the development of arterial aneurysm formation ( Cooper et al, 2021 ; van der Pluijm et al, 2018 ; Oller et al, 2021 ). A single-cell transcriptome analysis on aneurysmal human aortic tissue suggested that mitochondrial dysfunction and increased chromatin oxidative phosphorylation (OXPHOS) were found in TAA tissues and insufficient ATP production might not be sufficient for the contractile activities of human aortic smooth muscle cells (HAoSMCs) ( Li et al, 2020 ).…”

Therapeutic Potential of Emerging NAD+-Increasing Strategies for Cardiovascular Diseases

“…The pharmacologic potential of NR in TAAs associated with genetic disorders has been investigated [ 221 ]. Using a mouse model with specific deletion of mitochondrial transcription factor A ( Tfam ) in VSMCs, Tfam -deficient VSMCs were observed to acquire a senescent and proinflammatory phenotype together with impairment in their contractile function [ 221 ].…”

“…The pharmacologic potential of NR in TAAs associated with genetic disorders has been investigated [ 221 ]. Using a mouse model with specific deletion of mitochondrial transcription factor A ( Tfam ) in VSMCs, Tfam -deficient VSMCs were observed to acquire a senescent and proinflammatory phenotype together with impairment in their contractile function [ 221 ]. These mice develop aortic aneurysms, medial degeneration, and lethal dissections, and NR supplementation rapidly raised TFAM levels, improved mitochondrial metabolism, and normalized aortic function and diameter in the Marfan mouse model of TAA.…”

Aorta-on-a-chip reveals impaired mitochondrial dynamics as a therapeutic target for aortic aneurysm in bicuspid aortic valve disease

“…Mitochondrial dysfunction has been closely linked to a variety of cardiovascular disorders, such as heart failure and atherosclerosis. Recent studies found that mitochondrial dysfunction was also related to the development of arterial aneurysm formation ( Cooper et al, 2020; van der Pluijm et al, 2018; Oller et al, 2021 ). A single-cell transcriptome analysis on aneurysmal human aortic tissue suggested that mitochondrial dysfunction and increased chromatin oxidative phosphorylation (OXPHOS) were found in TAA tissues and insufficient ATP production might not be sufficient for the contractile activities of human aortic smooth muscle cells (HAoSMCs) ( Li et al, 2020 ).…”