Ex vivo models to decipher the molecular mechanisms of genetic Notch cardiovascular disorders

Notch is an evolutionary conserved cell-cell signaling pathway that is central in several biological processes, from tissue morphogenesis to homeostasis. It is therefore not surprising that several genetic mutations of Notch components cause inherited human diseases, especially cardiovascular disorders. Despite numerous efforts, current in vivo models are still insufficient to unravel the underlying mechanisms of these pathologies, hindering the development of utmost needed medical therapies. In this perspective review we discuss the limitations of current murine models and outline how the combination of microphysiological systems and targeted computational models can lead to breakthroughs in this field. In particular, while microphysiological systems enable the experimentation on human cells in controlled and physiological environments, in silico models can provide a versatile tool to translate the in vitro findings to the more complex in vivo setting. As a showcase example, we focus on Notch-related cardiovascular diseases, such as Alagille syndrome, Adams-Oliver syndrome, and CADASIL.