Reversing vessel instability: characterization of new molecular targets to struggle Hereditary Haemorrhagic Telangiectasia

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2023 Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant genetic disease that affects the blood vessels, leading to their abnormal development. The mutations responsible for this disease primarily impact the TGF-β pathway, a key player in vessel formation. The primary cell types involved in the vasculature are endothelial cells (EC) and smooth muscle cells (SMC). HHT mutations disrupt the normal functions of the TGF-β pathway, resulting in abnormal EC proliferation, migration and impaired recruitment of SMC towards ECs. This, in turn, leads to the formation of immature and leaky vessels. SMCs are exceptionally intriguing and important cells that play a critical role in the vessel homeostasis. They exhibit remarkable elasticity and can undergo a phenotypic switch when necessary. Under normal conditions, SMCs have a contractile, differentiated, and non-proliferative phenotype. However, in pathologic conditions, SMCs transition to a de-differentiated state, becoming non-contractile and exhibiting a disorganized cytoskeleton, which allow them to proliferate and migrate. Importantly, this SMC phenotypic switch can be reversible, enabling them to respond to physiological and environmental demands. Proper interaction and robust cellular communication are fundamental for the development of mature and healthy vessels. Nevertheless, the molecular mechanisms underlying the effects of HHT mutations on SMC biology and their implication in EC-SMC interaction remain poorly understood. Thus, this project aims to identify key genes that directly modulate the phenotypic switch of SMCs, as they are crucial targets for reversing their pathologic phenotype and improving vessel stabilization.