Endothelial-to-mesenchymal transition in the central nervous system: A potential therapeutic target to combat age-related vascular fragility.

Age-related dysfunction of the central nervous system, including cognitive impairment and visual disorders, is a major concern for the aging population, affecting health span and quality of life. Age-related vascular dysfunction in the central nervous system includes an increase in blood-brain or blood-retina barrier permeability, an increase in vascular fragility, and impaired neurovascular coupling, contributing to cognitive impairment and vision loss. While these pathologies occur in the brain and eye with age, gaps remain in our understanding of the underlying cellular mechanisms. During the process of endothelial-to-mesenchymal transition (EndMT), endothelial cells lose their characteristic endothelial phenotypes, which are critical for vascular function, such as barrier integrity, and transition to a mesenchymal-like phenotype. EndMT is triggered by many age-related stimuli and is involved in the progression of many age-related diseases (eg, atherosclerosis, cardiovascular disease, etc). Here, we review what is known about the role of EndMT in vascular fragility in the aging brain and eye, explore the mechanistic links between endothelial cell transdifferentiation and age-associated vascular pathologies of the central nervous system, and identify potential therapeutic targets ripe for future exploration with the goal of preserving vascular function with aging by regulating EndMT. SIGNIFICANCE STATEMENT: Endothelial-to-mesenchymal transition is a key form of cellular plasticity that leads to disrupted barrier function and vascular disorders. Here, we evaluate what is known about this process in the brain, highlight potential targetable mechanisms to block it, and identify areas where further research is needed.