Thesis defense Milène Fréneau

https://umr1087.univ-nantes.fr/medias/photo/freneau-milene-4-_1672913391050-jpg
  • Le 08 March 2023
    Amphi DE
    false false
  • 13h30

Title of the thesis : Role of rare genetic variants of ANGPTL6 and CTSO in intracranial aneurysm formation

Equipe

Team III - Vascular & Pulmonary Diseases


Directeur de thèse

Gervaise Loirand


Co-encadrante

Anne Clémence Vion


Rapporteurs

Anne JOUTEL, MD, PhD, Inserm U1266,  Institut de Psychiatrie et Neurosciences de Paris
Patrick LACOLLEY, MD, PhD, Inserm U1116, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine


Examinateurs

Yacine BOULAFTALI, PhD, Inserm U1148 - Laboratory for Vascular Translational Science (LVTS), Université Paris Cité / Sorbonne Paris Nord
Romain BOURCIER, MD, PhD, Inserm UMR 1087/CNRS UMR 6291, CHU de Nantes, Nantes Université
Sandrine MOREL, PhD, Université de Genève (Département de pathologie et d'immunologie)
 

Keywords : intracranial aneurysm, smooth muscle cell, ANGPTL6, CTSO

 

Abstract

An intracranial aneurysm (IA) is a local dilatation of the cerebral arteries. Its rupture causes a subarachnoid haemorrhage which is fatal in 40% of cases and leads to severe disabilities in half of the survivors. IA affects 3% of the general population and familial forms represent 10% of cases.

Using whole exome sequencing approach in familial forms of IA, our laboratory identified two genes in which rare variants were present in affected members: ANGPTL6 and CTSO, variants predicted to be damaging for their function. These genes encode for angiopoietin-like 6 (ANGPTL6) and cathepsin O (CTSO) respectively. ANGPTL6 is a circulating glycoprotein secreted by the liver and has a role in developmental angiogenesis, the identified Δ-ANGPTL6 variant impairs its secretion. CTSO is a cysteine protease with an unknown substrate, but other cathepsins are known to be involved in vascular remodelling and overexpressed in IA. The aim of this study is to identify the role of these two proteins in cerebral arteries and IA formation.

Generation of a mouse model expressing the Δ-ANGPTL6 variant and in vitro analyses in vascular smooth muscle cells (VSMC) showed that mutant mice exhibit endothelial dysfunction, focal dilatations of cerebral arteries and impaired angiogenesis due to delayed recruitment of VSMC. In vitro, ANGPTL6 contributes to adhesion and reduces VSMC migration. Analysis of CTSO shows that in the arterial wall, the protein is predominantly expressed in VSMC and its secretion is stimulated by stretch. Depletion of CTSO in VSMC accelerates their adhesion to a fibronectin matrix, promotes their contractile phenotype and increases fibronectin expression. Overexpression of CTSO variants, compared to the wild type, also induces an increase in fibronectin expression. These data suggest that CTSO may degrade fibronectin and that the identified variants lose this ability.

This work provides the basis for understanding the mechanisms by which ANGPTL6 and CTSO variants predispose to IA.

Mis à jour le 02 June 2023.
https://umr1087.univ-nantes.fr/research/research-teams/soutenance-de-these-milene-freneau