NON-ATHEROMATOUS AORTOPATHIES : FROM GENETICS TO NEW PATHOPHYSIOLOGICAL AND THERAPEUTIC CONCEPTS – NONAGES

Thoracic aortic aneuryms are usually asymptomatic diseases with life-threatening complications of rupture and/or dissection. Classical risk factors may favour their progression, but inheritance is playing a major role and guidelines recommend aortic imaging in first-degree relatives of on affected subject. Although several causative genes have already been identified, the understanding of biological mechanisms and consequences has to be improved to translate knowledge into new therapeutic strategies. Our project aims at advancing basic knowledge, at developing and validating new biomarkers and imaging protocols and possible preventive therapies.
We have a large clinical database of patients with familial TAAD (Thoracic Aortic Aneurysm and Dissection) in whom bio- and tissue-banking was performed, allowing for recognition of new disease genes using whole exome sequencing (informative families are being studied by WES) combined with downstream molecular, tissue and cellular analyses for replication and validation. This should allow elucidation of pathogenic mechanisms and the identification of new biological pathways responsible for this pathology. Similarly, because we have wide and precise phenotyping of more than 1000 patients with Marfan Syndrome (MFS) carrying a mutation at the FBN1 gene, we will search for modifier genes (extreme variability is observed in this population) using both WES and genomewide phenotyping. We also have a unique database of patients with vascular Ehlers Danlos Syndrome (vEDS)
We have also the largest biobank worldwide of aortic tissue obtained during surgery in patients with TAAD of various origin (>800), and normal aortic tissue (100). This will allow evaluation of alteration of aortic wall permeability (proteomics of conditioned media), activation of proteolysis within the aortic wall (we previously showed that fibrinolysis is activated within the aortic wall in TAAD, and will focus on S100 proteins), evaluation of the protease / antiprotease clearance within the aortic wall by the smooth muscle cells (determining the aortic wall change), and retention of proteins within the aortic wall (particularly in the areas of mucoid degeneration).
The biobank also includes plasma and serum allowing the search for new biomarkers. We will look at. markers of the ECM metabolism, particularly type III collagen vEDS patients. We will validate preliminary results, including the diagnostic and prognostic potential for miRs in vEDS and MFS, and study the potential value of markers of the TGF-B pathway and fibrinolysis in these patients. During chronic dissection of the descending aorta, we will evaluate the value of D-Dimers for predicting evolution of the patients (our preliminary results indicate that the presence of thrombus favours dilatation in these patients).
Our imaging team will evaluate the potential of new probes (for plasmin and for elastase) to detect and quantify the proteolytic activity within the aortic wall in mouse models for Marfan syndrome or vEDS which are available in our group. These evaluations will be made after sensitisation by angiotensin II infusion, and will also be performed after inhibition of plasmin. This preclinical step should pave the way for clinical evaluation in patients.
The understanding we have of the remodelling process of the aortic wall during aortic dilatation and before aortic dissection suggests that the importance of environmental factors should be tested, especially periodontal infections for the occurrence of arterial events in vEDS patients, or vitamin C supplementation in vEDS with mutations leading to haploinsufficiency. We will use diverse animal models we have (Col3a1 KI mice prone to dissection, Fbn1 KI mice prone to dilatation) to study the impact of vasoactive agents, both protective (Sartans, beta-blockers) or potentially deleterious (angiotensin II). Lastly we would like to evaluate the potential of plasmin inhibition to limit aortic dissection in these mode