Summary The blood-brain barrier (BBB) provides a constant homeostatic brain environment that is essential for proper neural function. An unusually low rate of vesicular transport (transcytosis) has been identified as one of the two unique properties of central nervous system (CNS) endothelial cells, relative to peripheral endothelial cells, that maintain the restrictive quality of the BBB. However, it is not known how this low rate of transcytosis is achieved. Here we provide a mechanism whereby the regulation of CNS endothelial cell lipid composition inhibits specifically the caveolae-mediated transcytotic route readily used in the periphery. An unbiased lipidomic analysis reveals significant differences in endothelial cell lipid signatures from the CNS and periphery, which underlie a suppression of caveolae vesicle formation and trafficking in brain endothelial cells. Furthermore, lipids transported by Mfsd2a establish a unique lipid environment that inhibits caveolae vesicle formation in CNS endothelial cells to suppress transcytosis and ensure BBB integrity.

The blood-brain barrier (BBB) maintains the optimal microenvironment in the central nervous system (CNS) for proper brain function. The BBB is comprised of specialized CNS endothelial cells with fundamental molecular properties essential for the function and integrity of the BBB. The restrictive nature of the BBB hinders delivery of therapeutics for many neurological disorders. In addition, recent evidence shows that BBB dysfunction can precede or hasten the progression of several neurological diseases. Despite the physiological significance of the BBB in health and disease, major discoveries of the molecular regulators of BBB formation and function have only occurred recently. This review will highlight recent findings describing the molecular determinants and core cellular pathways that confer BBB properties upon CNS endothelial cells.

No abstract

Summary Proper brain function depends on neurovascular coupling: neural activity rapidly increases local blood flow to meet moment-to-moment changes in regional brain energy demand 1 . Neurovascular coupling is the basis for functional brain imaging 2 , and its impairment is implicated in neurodegeneration 1 . The underlying molecular and cellular mechanisms of neurovascular coupling remain poorly understood. The conventional view is that neurons or astrocytes release vasodilatory factors that act directly on smooth muscle cells (SMC) to induce arterial dilation and increase local blood flow 1 . Here, using two-photon microscopy to image neural activity and vascular dynamics simultaneously in the barrel cortex of awake mice under whisker stimulation, we found that arteriolar endothelial cells (aECs) play an active role in mediating neurovascular coupling. We found that aECs, unlike other vascular segments of ECs in the CNS, have abundant caveolae. Acute genetic perturbations that eliminated caveolae in aECs, but not in neighboring SMCs, impaired neurovascular coupling. Strikingly, caveolae function in aECs is independent of the eNOS-mediated nitric oxide (NO) pathway. Ablation of both caveolae and eNOS completely abolished neurovascular coupling, whereas each single mutant exhibited partial impairment, revealing that caveolae-mediated pathway in aECs is a major contributor to neurovascular coupling. Our findings indicate that vasodilation is largely due to ECs that actively relay signals from the CNS to SMCs via a caveolae-dependent pathway.