Brain Endothelial Cells in Blood-Brain Barrier Regulation and Neurological Therapy

Abstract

Brain endothelial cells (BECs) constitute the core component of the blood-brain barrier (BBB), regulating substance exchange between blood and the brain parenchyma to maintain central nervous system homeostasis. In pathological states, the BBB exhibits the disruption of tight junctions, endothelial cell (EC) damage, and increased permeability, accompanied by neuroinflammation, oxidative stress, and abnormal molecular signaling pathways, leading to neurotoxic effects in the brain parenchyma and exacerbating neurodegeneration and disease progression. This review systematically summarizes the developmental origin, structural characteristics, and pathological mechanisms of BECs in diseases such as Alzheimer's disease, multiple sclerosis, stroke, and glioblastoma with a particular focus on the regulatory mechanisms of the Wnt/β-catenin and VEGF signaling pathways. By integrating the latest research advances, this review aims to provide a comprehensive perspective for understanding the role of BECs in physiological and pathological states and to provide a theoretical basis for the development of BBB-based therapeutic approaches for neurological diseases.

Keywords: blood–brain barrier; brain endothelial cells; neurological disorders; signaling pathways; therapeutic strategies.

Figure 1

Molecular regulation of BBB and fenestrated vasculature. Schematic representation of two molecular regulation pathways involved in the formation of the BBB and the fenestrated vasculature [49]. Endothelial progenitor cells have the potential to differentiate into distinct endothelial subtypes depending on the microenvironmental cues and signaling pathways. Specifically, they can give rise to (1) barrier-forming brain microvascular ECs that contribute to the BBB, a process predominantly driven by Wnt/β-catenin signaling. Alternatively, (2) under the influence of VEGF signaling, these progenitor cells can differentiate into specialized fenestrated ECs (fenestrated ECs), such as those found in choroid plexus.

Figure 2

Multi-target therapeutic strategies for BBB repair. Schematic presentation of BBB treatment by targeting the Wnt signaling pathway, anti-inflammatory factors, and mitochondria. (1) The Wnt7a/b—Gpr124/Reck co-receptor complex binds to Frizzled receptors, activating the Wnt signaling pathway to restore BBB integrity. (2) Inflammatory signaling activates NF-κB, leading to the downregulation of tight junction proteins (ZO-1, occludin, etc.) and subsequent BBB impairment. Metformin counteracts this process by suppressing NF-κB activation through AMPK pathway stimulation. (3) Therapeutic antioxidant-loaded T807/TPP-RBC-NPs demonstrate direct mitochondrial targeting capability in neurons, effectively reducing oxidative stress to alleviate pathological symptoms. Future development should focus on engineering nanoparticles specifically targeting endothelial cell mitochondria within the BBB.

Figure 3

Multifaceted therapeutic strategies targeting the BBB. Schematic representation of therapeutic strategies targeting EC regulation, drug delivery optimization, and genetic interventions, providing precision treatment options for neurological disorders. Current BBB restoration strategies implement synergistic multidimensional approaches: (1) Pathway modulation—Wnt7a/β-catenin activation to enhance tight junction integrity and metformin-mediated AMPK/NF-κB axis inhibition to attenuate inflammation; (2) Mitochondrial remediation—antioxidant therapies combined with metabolic stabilization to address dysfunction; (3) Delivery innovations—engineered nanocarriers (liposomes, PLGA nanoparticles, and TfR-targeted platforms) for BBB-penetrant drug transport, alongside microbubble-assisted focused ultrasound for transient barrier opening validated in preclinical/clinical settings; (4) Cellular/genetic interventions—EPCs for vascular repair and CRISPR-Cas9-driven transporter gene editing to optimize cerebral drug biodistribution and efficacy.