Mechanisms Underlying Neurovascular Interactions: Blood-Brain Barrier and Neurovascular Coupling

Abstract

To continuously compute neural activity for perception, motor movements and cognition, the central nervous system (CNS) requires a homeostatic microenvironment that is not only enriched in nutrients to meet its high metabolic demands but also devoid of toxins to prevent harm to the sensitive neural tissue. To establish and maintain this highly regulated microenvironment, the CNS has induced its vasculature to evolve two functions absent in the vasculature of peripheral organs: 1) blood-CNS barrier formation and 2) neurovascular coupling. Blood-CNS barriers partition the circulating blood from the CNS and regulate the selective trafficking of substances between the blood and the CNS. Neurovascular coupling ensures that following local neural activation, regional blood flow increases quickly to supply more nutrients and dispel metabolic waste. The goal of this dissertation is to show how the CNS vasculature acquires, maintains and executes these two functions for optimal neural function. First, we provide a mechanism of how the CNS vasculature forms the blood-CNS barrier during development. Using a combination of mouse genetics, light and electron microscopy, we showed that nascent CNS vessels initially lack a blood-CNS barrier. However, through development, they gradually acquire barrier properties from the neural environment. Specifically, we identified that nascent CNS vessels already have functional tight junctions but display bulk transcytosis, resulting in the immature barrier. However, through development, nascent CNS vessels gradually suppress transcytosis and eventually form a functional blood-CNS barrier. Second, we demonstrate that CNS arteriolar endothelial cells (aECs), a segment of the CNS vasculature, play an active role to mediate neurovascular coupling. Using mouse genetics, two-photon imaging, electron and light microscopy, we find that aECs, unlike other segments of endothelial cells in the CNS vasculature, have abundant caveolae. CNS aECs use caveolae to mediate neurovascular coupling, as ablation of caveolae specifically in aECs disrupts neurovascular coupling. Furthermore, this caveolae-mediated pathway is independent of the eNOS-mediated pathway. Finally, we find that Mfsd2a, a suppressor of caveolae in capillary endothelial cells to ensure functional blood-CNS barrier integrity, is absent in aECs. Ectopic expression of Mfsd2a in CNS aECs deters caveolae formation and concurrently, impairs neurovascular coupling.