Brain endothelial homeostasis in psychiatric disorders: mechanisms, evidence, and translational opportunities

Brain endothelial cells (BECs) are specialized components of the neurovascular unit that couple circulating signals to cerebral blood flow regulation, blood-brain barrier (BBB) function, and selective molecular transport. This narrative review evaluates the correlation of these endothelial functions with psychiatric disorders, including depression and schizophrenia, distinguishing established vascular physiology from disease-specific evidence. In neurovascular coupling, the functions of capillary Kir2.1/phosphatidylinositol 4,5-bisphosphate and ATP-sensitive K⁺ channels, TRPA1-PANX1-P2X signaling, inositol 1,4,5-trisphosphate receptor-mediated Ca²⁺ events, arterial GJA4/GJA5 coupling, and PIEZO1-mediated mechanical feedback vary depending on the vascular segment. At the BBB, CLDN5, OCLN, F11R, TJP1, CDH5, the actin cytoskeleton, MFSD2A, and selective influx and efflux transporters determine paracellular permeability and transcytosis. Cerebral fluid and solute clearance should be separated into perivascular cerebrospinal fluid/interstitial fluid exchange, BBB transport, and meningeal lymphatic or venous drainage. BECs contribute to vascular and transporter interfaces but are not demonstrated to be the central drivers of glymphatic flow. Stress-related, sex-dependent, and brain region-dependent changes in CLDN5 and endothelial inflammatory signaling are reported to be strongly correlated with psychiatric disorders. In contrast, studies on serum biomarkers, postmortem tissues, patient-derived models, and animals provide different and non-equivalent levels of inference. Clinical trials have not evaluated a BEC-directed therapy for a primary psychiatric disorder. Future studies must focus on developing endothelial-specific and vascular segment-specific interventions, identifying prospective human BBB or cerebrovascular biomarkers, performing analysis according to sex and brain region, and systematically assessing peripheral vascular and barrier-related safety.