Thesis defense Mary Adel Mrad

Equipe

Team III - Vascular & Pulmonary Diseases

Directrice de thèse

Gervaise Loirand

Co-directrice 

Anne-Clémence Vion
 

Rapporteurs

Nicolas Borghi, PhD, Directeur de recherche, Institut Jacques Monod, Université Paris Cité, CNRS
Damien Ramel, PhD, Chargé de recherche, I2MC INSERM

Examinatrices

Catherine LEMARIE, PhD, Chargée de recherche, GETBO Groupe d'étude de la thrombose de Bretagne occidentale
Catherine Coirault, PhD, Directrice de recherche, Inserm

Abstract

Hemodynamic forces are essential regulators of vascular development and homeostasis. Within the arterial wall, cyclic stretch generated by pulsatile blood pressure is primarily sensed by vascular smooth muscle cells (VSMCs), which regulate their contractile and synthetic activities to maintain vessel tone and structural integrity. When these mechanical cues are altered, they can trigger deleterious arterial wall remodeling processes associated with vascular diseases, such as hypertension. Among the signaling pathways governing VSMC adaptation to mechanical stress, RhoA plays a pivotal role in controlling cytoskeletal organization and contractility. Yet, the upstream mechanosensitive guanine nucleotide exchange factors (GEFs) that regulate RhoA activation in VSMCs remain poorly defined. RNA sequencing of normotensive and hypertensive arteries, as well as VSMCs subjected to varying levels of cyclic stretch, identified NET1/ARHGEF8 as a potential mechanosensitive GEF. In VSMCs, physiological stretch (10% elongation) increased NET1 expression, promoted its cytoplasmic relocalization, and enhanced its interaction with RhoA. Silencing NET1 decreased MYPT1 phosphorylation and impaired cell adhesion and spreading without affecting proliferation. Conversely, forced cytoplasmic localization of NET1 increased the expression of contractile markers and enhanced both spontaneous and agonist-induced contraction, whereas nuclear retention of NET1 diminished these effects.
Collectively, these findings establish NET1 as a potential stretch-sensitive RhoGEF that plays a role in VSMC physiology.