Endothelial β-Catenin Signaling Is Required for Maintaining Adult Blood–Brain Barrier Integrity and Central Nervous System Homeostasis

Abstract

Background The blood-brain barrier (BBB) formed by brain endothelial cells (ECs) interconnected by tight junctions (TJs) is essential for the homeostasis of the central nervous system (CNS). Although studies have shown the importance of various signaling molecules in BBB formation during development, little is known about the molecular basis regulating the integrity of the adult BBB. Methods and Results Using a mouse model with tamoxifen-inducible EC-restricted disruption of ctnnb1 (iCKO), here we show that endothelial β-catenin signaling is essential for maintaining BBB integrity and CNS homeostasis in adult. The iCKO mice developed severe seizures accompanied by neuronal injury, multiple brain petechial hemorrhages, and CNS inflammation, and all died postictal. Disruption of endothelial β-catenin induced BBB breakdown and downregulation of specific TJ proteins Claudin-1 and -3 in adult brain ECs. The clinical relevance of the data is indicated by the observation of decreased expression of Claudin-1 and nuclear β-catenin in brain ECs of hemorrhagic lesions of hemorrhagic stroke patients. Conclusion These results demonstrate the prerequisite role of endothelial β-catenin in maintaining the integrity of adult BBB. The results suggest that BBB dysfunction secondary to defective β-catenin transcription activity is a key pathogenic factor in hemorrhagic stroke, seizure activity and CNS inflammation.

Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis

“…sTg, n = 7; dTg, n = 7. **P < 0. the adult BBB (35,71,72). Here we provide in vivo evidence that the Wnt/β-catenin pathway becomes highly activated in CNS endothelium during both EAE and human MS during the course of disease progression.…”

“…Loss of Wnt/β-catenin signaling in developing blood vessels disrupts CNS angiogenesis and prevents BBB formation (32)(33)(34). Although Wnt signaling is reduced in CNS blood vessels once the barrier is fully formed, this pathway is essential to maintain barrier properties in the adult CNS (35). Activation of Wnt/ β-catenin signaling has been reported in some neuroinflammatory Significance Endothelial cells (ECs) in the CNS form a unique blood-brain barrier (BBB) that is broken down in multiple sclerosis (MS).…”

Junctional proteins of the blood-brain barrier: New insights into function and dysfunction

“…71,72 The cytoplasmic AdJ proteins are a complex of p120, b-catenin and plakoglobin which further bind to a-catenin, and AdJ bridging proteins for AdJ protein interaction with actin binding proteins, ZO-1, and actin filaments. 2,73 Although the models by which the cytoplasmic catenin complex associates with Ve-cadherin and the cytoskeleton are still controversial, catenin is important for both the adhesive properties of V-cadherin and actin bundling, controlling endothelial barrier permeability. 13 …”

An integrative microfluidically supported in vitro model of an endothelial barrier combined with cortical spheroids simulates effects of neuroinflammation in neocortex development

“…In hCMEC/D3 cell layers, we analysed the expression of von Willebrand factor (vWF), a protein that is involved in regulation of coagulation and moreover is a central regulator of permeability and flexibility of the endothelial cell layer within the BBB. 18 In addition, we examined the expression of VE-cadherin and b-catenin, proteins required for the maintenance of endothelial barrier integrity and CNS homeostasis, 19 as well as the tight junction protein ZO-1. We observed no alterations in the protein expression of these proteins during adaption and subsequent culture of CMEC in CTM/ECM medium compared with ECM medium (Figure 4(b)).…”

“…HCMEC/D3 cell layers expressed central marker proteins known to regulate BBB integrity and flexibility in vivo, such as vWF, VE-cadherin, ZO-1, and b-catenin. [4][5][6]9,10,18,19 Furthermore, this model is able to reflect critical aspects of neuroinflammation, as depicted by its ability to specifically reproduce a cytokineinduced disruption of the endothelial barrier associated with subsequent alterations in neural cell morphology, increased neural cell death, and diminished expression of neural differentiation marker proteins. Our results are in agreement with the findings from studies in mice that analysed the development of the neocortex under inflammatory conditions.…”