doi:10.1073/pnas.1614777114. disorders, and acute CNS disorders such as stroke, traumatic brain injury, spinal cord injury, and epilepsy. Lastly, we discuss BBB-based therapeutic opportunities. We conclude with lessons learned and future directions, with emphasis on technological advances to investigate the BBB functions in the living human brain, and at the molecular and cellular level, and address key unanswered questions. I. INTRODUCTION The blood-brain barrier (BBB) prevents neurotoxic plasma components, blood cells, and pathogens from entering the brain (420). At the same time, the BBB regulates transport of molecules into and out of the central nervous system (CNS), which maintains tightly controlled chemical composition of the neuronal milieu that is required for proper neuronal functioning (682, 693). In disease says, BBB breakdown and dysfunction leads to leakages of harmful blood components into the CNS, cellular infiltration, and aberrant transport and clearance of molecules (420, 682, 693), which is usually associated with cerebral blood flow (CBF) reductions and dysregulation (269C271, 318), contributing to neurological deficits. The pattern of cerebral blood vessels follows the major brain circuits tasked with sensation, memory, and motion suggesting that this cerebrovascular system plays PROTAC MDM2 Degrader-3 an important role in normal CNS functioning (271, 318, 682). Under physiological conditions, the human brain receives 20% of the cardiac output and uses 20% of the bodys oxygen and glucose (270). Energy substrates are consumed by the brain on the travel from blood via transport across the BBB, as the brain lacks a reservoir to store fuel for use when needed (271). In the mammalian brain, cerebral arteries, arterioles, and capillaries supply CNS circuits with blood in response to neuronal stimuli by increasing the rate of CBF and oxygen delivery, a mechanism known as neurovascular coupling (271, 319). Different cell types of the neurovascular unit (NVU) including vascular cells [e.g., endothelium and mural cells including pericytes and easy muscle cells (SMCs)], glia (e.g., astrocytes, microglia), and neurons contribute to regulation of BBB permeability, neurovascular coupling, cell-matrix interactions, neurotransmitter turnover, and angiogenesis and neurogenesis (270, 271, 692, 693) (FIGURE 1). PROTAC MDM2 Degrader-3 Open in a separate window Physique 1. The neurovascular unit. embryos lacking lipolysis-stimulated lipoprotein receptor (LSR), a component of tricellular junctions, exhibit a BBB open to molecules that are ~10 kDa (551). The mice with haploid deficiency in glucose transporter GLUT1 in brain endothelial cells develop microvascular reductions with BBB breakdown including loss of TJ and basement membrane proteins (649), whereas knockout of murine gene results in not only diminished brain uptake of docosahexaenoic acid (DHA) in the form of lysophosphatidylcholine, but also leads to dysregulated caveolae-mediated transcellular trafficking across the BBB causing BBB breakdown (21, 62, 684). Neurological consequences of these BBB genetic defects are discussed below. B. BBB Maturation and Maintenance The BBB continues to mature under PROTAC MDM2 Degrader-3 the influence of neural environment after day E15 in mice and over a brief period after birth (682). Astrocytes join the NVU during the maturation stage and provide additional support, including the formation of perivascular astrocytic endfeet around capillaries and the glial limitans that ensheathes the penetrating arterioles (682). Astrocytes also strengthen the basement membrane by producing laminin 1 and 2, which are important for stabilizing pericytes (667). In addition, astrocytes secrete retinoic acid and SHH, which transcriptionally regulates gene expression Rabbit Polyclonal to SFRS17A in endothelial cells and enhances the formation of intercellular junction functions (13). Endothelial-pericyte PDGF-BB-PDGFR signaling pathway, pericyte-endothelial TGF- and Ang-1-Tie-2 signaling pathways, as well as astrocyte-endothelial SHH pathway, angiotensin II-AT1 receptor and Wnt-Frizzled signaling pathways, continue to influence the BBB maturation. The close interactions between the NVU cells are critical for the maintenance of the BBB. For example, astrocytes secrete apolipoprotein E (APOE) to signal pericytes via low-density lipoprotein receptor-related protein-1 (LRP1), which suppress the activation of cyclophilin A (CypA)-matrix metalloproteinase 9 (MMP-9) BBB-degrading pathway,.