Significance: Development of the blood–brain barrier (BBB) requires spatiotemporal coordination of cerebrovascular endothelial cells (ECs) and pericytes. Until now, the molecular mechanism(s) coordinating the pericyte–EC behaviors during this process have been incompletely understood. In this study, combining the analysis of EC-/pericyte-specific Cd146 -KO mice and in vitro BBB models, we report CD146 as a dynamic coordinator regulating the communication between ECs and pericytes within the neurovascular unit during BBB development. Our study demonstrates that a single cell-adhesion receptor, CD146, acts as an essential regulator to coordinate pericyte–EC communication and BBB formation during embryogenesis. Furthermore, it identifies CD146 as a potential key therapeutic target for neurological diseases related to cerebrovascular disorders.

Stroke is a devastating disease with high morbidity and mortality. Animal models are indispensable tools that can mimic stroke processes and can be used for investigating mechanisms and developing novel therapeutic regimens. As a heterogeneous disease with complex pathophysiology, mimicking all aspects of human stroke in one animal model is impossible. Each model has unique strengths and weaknesses. Models such as transient or permanent intraluminal thread occlusion middle cerebral artery occlusion (MCAo) models and thromboembolic models are the most commonly used in simulating human ischemic stroke. The endovascular filament occlusion model is characterized by easy manipulation and accurately controllable reperfusion and is suitable for studying the pathogenesis of focal ischemic stroke and reperfusion injury. Although the reproducibility of the embolic model is poor, it is more convenient for investigating thrombolysis. Rats are the most frequently used animal model for stroke. This review mainly outlines the stroke models of rats and discusses their strengths and shortcomings in detail.

Blood-brain barrier (BBB) disruption is a key event in triggering secondary damage to the central nervous system (CNS) under stroke, and is frequently associated with abnormal macroautophagy/autophagy in brain microvascular endothelial cells (BMECs). However, the underlying mechanism of autophagy in maintaining BBB integrity remains unclear. Here we report that in BMECs of patients suffering stroke, CLDN5 (claudin 5) abnormally aggregates in the cytosol accompanied by autophagy activation. In vivo zebrafish and in vitro cell studies reveal that BBB breakdown is partially caused by CAV1 (caveolin 1)-mediated redistribution of membranous CLDN5 into the cytosol under hypoxia. Meanwhile, autophagy is activated and contributes mainly to the degradation of CAV1 and aggregated CLDN5 in the cytosol of BMECs, therefore alleviating BBB breakdown. Blockage of autophagy by genetic methods or chemicals aggravates cytosolic aggregation of CLDN5, resulting in severer BBB impairment. These data demonstrate that autophagy functions in the protection of BBB integrity by regulating CLDN5 redistribution and provide a potential therapeutic strategy for BBB disorder-related cerebrovascular disease. Abbreviations: BBB: blood-brain barrier; BECN1: beclin 1; BMEC: brain microvascular endothelial cell; CAV1: caveolin 1; CCA: common carotid artery; CLDN5: claudin 5; CNS: central nervous system; CQ: chloroquine; HIF1A: hypoxia inducible factor 1 subunit alpha; MCAO: middle cerebral artery occlusion-reperfusion; OCLN: occludin; ROS: reactive oxygen species; STED: stimulated emission depletion; TEER: trans-endothelial electrical resistance; TEM: transmission electron microscopy; TJ: tight junction; TJP1: tight junction protein 1; UPS: ubiquitin-proteasome system

Zebrafish (Danio rerio) have attracted much attention over the past decade as a reliable model for gut microbiome research. Owing to their low cost, strong genetic and development coherence, efficient preparation of germ‐free (GF) larvae, availability in high‐throughput chemical screening, and fitness for intravital imaging in vivo, zebrafish have been extensively used to investigate microbiome‐host interactions and evaluate the toxicity of environmental pollutants. In this review, the advantages and disadvantages of zebrafish for studying the role of the gut microbiome compared with warm‐blooded animal models are first summarized. Then, the roles of zebrafish gut microbiome on host development, metabolic pathways, gut‐brain axis, and immune disorders and responses are addressed. Furthermore, their applications for the toxicological assessment of aquatic environmental pollutants and exploration of the molecular mechanism of pathogen infections are reviewed. We highlight the great potential of the zebrafish model for developing probiotics for xenobiotic detoxification, resistance against bacterial infection, and disease prevention and cure. Overall, the zebrafish model promises a brighter future for gut microbiome research.

The blood-brain barrier (BBB) is essential for the exchange of nutrient and ions to maintain the homeostasis of central nervous system (CNS). BBB dysfunction is commonly associated with the disruption of endothelial tight junctions and excess permeability, which results in various CNS diseases. Therefore, maintaining the structural integrity and proper function of the BBB is essential for the homeostasis and physiological function of the CNS. Here, we showed that serum starvation disrupted the function of endothelial barrier as evidenced by decreased trans-endothelial electrical resistance, increased permeability, and redistribution of tight junction proteins such as Claudin-5 (Cldn5). Further analyses revealed that autophagy was activated and protected the integrity of endothelial barrier by scavenging ROS and inhibiting the redistribution of Cldn5 under starvation, as evidenced by accumulation of autophagic vacuoles and increased expression of LC3II/I, ATG5 and LAMP1. In addition, autophagosome was observed to package and eliminate the aggregated Cldn5 in cytosol as detected by immunoelectron microscopy (IEM) and stimulated emission depletion (STED) microscope. Moreover, Akt-mTOR-p70S6K pathway was found to be involved in the protective autophagy induced by starvation. Our data demonstrated that autophagy played an essential role in maintaining the integrity of endothelial barrier by regulating the localization of Cldn5 under starvation.