Mechanisms of retinal vascular development

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BACKGROUND Blood vessels are among the first organs to develop in the embryo and are critical for tissue function and homeostasis. Postnatally, arteries and veins are considered terminally differentiated, but they retain enough plasticity to form new blood vessels. This NSERC program is built on a recent major breakthrough in the field: We discovered in the mouse retina, senescent cells (that age prematurely) producing a series of factors that contribute to vascular regrowth. Our preliminary data, also showed features of premature senescence in fetal transitory vessels, called hyaloids in developing eyes, that will regress after birth to be replaced by definitive retinal blood vessels. Interestingly, these senescent hyaloids of arterial origin are dynamic and can lose their original identity and acquire a vein identity. How developmental senescence partakes in arteriovenous identity switch during vascular eye development remains unanswered. My LONG-TERM GOAL is to decipher the cellular and molecular mechanisms that initiate and regulate senescence in the developing eye, and determine how this process influences endothelial cell (EC) plasticity as needed for vascular growth in homeostatic conditions. Based on solid preliminary data (published and not yet published), this work will test the general hypothesis that senescence in fetal hyaloid vessels is needed not only for their regression but also for the subsequent growth of definitive retinal vessels. For the next five years, my research program will revolve around the following SHORT-MID TERM GOALS: 1. Identify hyaloid and retinal EC sub-populations and the mechanisms regulating their identity. (Short-term goal) 2. Determine whether developmental senescence is required for arteriovenous specification. (Short and mid-term goal) 3. Determine cellular senescence distribution in hyaloid cells and its role in arteriovenous specification. (Future work). CONCLUSION: This multidisciplinary program will reveal a new facet of the biological functions of unconventional beneficial senescence. Research laboratories in the vision field focus on studying the most abundant cells in the retina (photoreceptors, neurons and immune cells). Yet, there is a wealth of evidence pointing to a significant role of the vascular component in the functioning of the eye. To bridge this gap of knowledge, my research program will decipher the cellular and molecular mechanisms responsible for the control of vascular cell identity and function in embryonic and adult retinal vessels. We expect to be pioneers in investigating the role of unconventional developmental senescence in eye blood vessels plasticity, characterized by arteriovenous specification. This NSERC research program will bring an entirely new way of thinking about blood vessel formation and holds a lot of promises to be more widespread than previously thought and could pave the way to study such mechanisms in other vascularized tissues.