DeClocking the vascular rhythmic control of tissue homeostasis and disease initiation

forthcoming

A quiescent, resilient layer of blood vessel-lining endothelial cells (ECs) is vital for maintaining organ function and enabling healthy aging. Much has been learnt in recent years about the mechanisms controlling the resilient EC phenotype. In turn, little is known if and how mechanisms of vascular resilience are affected by environmental rhythmic stimuli (extrinsic (e.g., light-dark, feeding-fasting) or intrinsic (e.g., blood pressure, hematopoiesis)). Performing day/night analyses of mouse liver and lung ECs, we identified distinct organ-specific time-of-the-day dependent transcriptomic programs of resting ECs. These translated functionally into temporal vascular adaptations during the day that critically sustain steady-state tissue health and function. Building on these stage-setting findings, the Vascular-Rhythm project will (i) analyze how ECs sense, adapt, and respond to circadian changes by uncovering rhythmic programs in healthy liver and lung ECs at mRNA, protein, and phospho-protein levels, and (ii) examine how the manipulation of vascular rhythms impacts physiological organ function, organismic aging, and disease initiation. To this end, we will implement a cross-species analytical platform (i.e., comparing nocturnal mice and diurnal pigs), integrate multiomics data with state-of-the-art computational methods, and perform in vitro & in vivo manipulatory assays to discover dynamic gene programs that underlie the homeostatic vascular endothelium and its adaptation to pathologic challenges. Collectively, adding the day/night cycle as a critical, hitherto in the field of vascular research heavily underappreciated research dimension, the Vascular-Rhythm project will fundamentally change the way we study and mechanistically understand blood vessel function. Moreover, the expected groundbreaking discoveries of the project have great potential to identify and validate novel therapeutic vascular vulnerabilities for multiple, circadian rhythm-affected pathologies.