Critical role of actin in modulating BBB permeability

Lai, Char-Huei; Kuo, Kuo‐Hsing; Leo, Joyce M.

doi:10.1016/j.brainresrev.2005.03.007

Cited by 112 publications

(90 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To confirm this finding, we examined the activities of the two pathways in HRMECs, which are the major players that undergo dysregulation of tight junction integrity by VEGF, leading to breakdown of inner blood-retinal barrier and eventually to retinal vascular hyperpermeability (34). To this end, we measured VEGF-induced mRNA expression of CD14 and ␤2 integrin genes in confluent HRMECs on F2 and FN1-coated dish, respectively, using RT-PCR analysis (see under "Experimental Procedures").…”

Section: Molecular and Cellular Proteomics 155mentioning

confidence: 97%

“…Retinal Proteome Profile Representing VEGF-induced Vascular Hyperpermeability-VEGF-induced vascular hyperpermeability and leakage have been shown to be associated with a loss of tight junction integrity between endothelial cells in the retina (33)(34)(35). The tight junction complexes consist of proteins spanning the intercellular cleft, such as occludin and claudin, and junctional adhesion molecules (33)(34)(35).…”

Section: Molecular and Cellular Proteomics 155mentioning

confidence: 99%

“…The tight junction complexes consist of proteins spanning the intercellular cleft, such as occludin and claudin, and junctional adhesion molecules (33)(34)(35). Interestingly, among the processes represented by cluster 2 (Fig.…”

Section: Molecular and Cellular Proteomics 155mentioning

confidence: 99%

“…Interestingly, among the processes represented by cluster 2 (Fig. 2C), actin cytoskeleton organization is closely linked to the tight junction integrity of endothelial cells because the actin cytoskeleton is connected with transmembrane proteins through zonula occludens proteins and cingulin in the cytoplasm (33,34). Furthermore, actin cytoskeleton modulates adherens junction dynamics through its binding to the vascular endothelial cadherin (12).…”

Section: Molecular and Cellular Proteomics 155mentioning

confidence: 99%

“…The integrity of the blood neural barriers is determined by the components of tight junction complexes in retinal endothelial cells (34). The proteins for which the expression was increased by VEGF treatment, but such alteration was inhibited by cotreatment of VEGF and anti-VEGF antibody (cluster 2 in Fig.…”

Section: Molecular and Cellular Proteomics 155mentioning

confidence: 99%

See 4 more Smart Citations

Quantitative Proteomics Reveals β2 Integrin-mediated Cytoskeletal Rearrangement in Vascular Endothelial Growth Factor (VEGF)-induced Retinal Vascular Hyperpermeability

Bae

Chae

et al. 2016

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

Retinal vascular hyperpermeability causes macular edema, leading to visual deterioration in retinal diseases such as diabetic retinopathy and retinal vascular occlusion. Dysregulation of junction integrity between endothelial cells by vascular endothelial growth factor (VEGF) was shown to cause retinal vascular hyperpermeability. Accordingly, anti-VEGF agents have been used to treat retinal vascular hyperpermeability. However, they can confer potential toxicity through their deleterious effects on maintenance and survival of neuronal and endothelial cells in the retina. Thus, it is important to identify novel therapeutic targets for retinal vascular hyperpermeability other than VEGF. Here, we prepared murine retinas showing VEGF-induced vascular leakage from superficial retinal vascular plexus and prevention of VEGF-induced leakage by anti-VEGF antibody treatment. We then performed comprehensive proteome profiling of these samples and identified retinal proteins for which abundances were differentially expressed by VEGF, but such alterations were inhibited by anti-VEGF antibody. Functional enrichment and network analyses of these proteins revealed the ␤2 integrin pathway, which can prevent dysregulation of junction integrity between endothelial cells through cytoskeletal rearrangement, as a potential therapeutic target for retinal vascular hyperpermeability. Finally, we experimentally demonstrated that inhibition of the ␤2 integrin pathway salvaged VEGF-induced retinal vascular hyperpermeability, supporting its validity as an alternative therapeutic target to anti-VEGF agents. Molecular & Cellular Proteomics

show abstract

Section: Molecular and Cellular Proteomics 155mentioning

confidence: 97%

Section: Molecular and Cellular Proteomics 155mentioning

confidence: 99%

Section: Molecular and Cellular Proteomics 155mentioning

confidence: 99%

Section: Molecular and Cellular Proteomics 155mentioning

confidence: 99%

Section: Molecular and Cellular Proteomics 155mentioning

confidence: 99%

See 3 more Smart Citations

Quantitative Proteomics Reveals β2 Integrin-mediated Cytoskeletal Rearrangement in Vascular Endothelial Growth Factor (VEGF)-induced Retinal Vascular Hyperpermeability

Bae

Chae

et al. 2016

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

show abstract

Bio‐Mimicking Brain Vasculature to Investigate the Role of Heterogeneous Shear Stress in Regulating Barrier Integrity

et al. 2022

View full text Add to dashboard Cite

A continuous, sealed endothelial membrane is essential for the blood–brain barrier (BBB) to protect neurons from toxins present in systemic circulation. Endothelial cells are critical sensors of the capillary environment, where factors like fluid shear stress (FSS) and systemic signaling molecules activate intracellular pathways that either promote or disrupt the BBB. The brain vasculature exhibits complex heterogeneity across the bed, which is challenging to recapitulate in BBB microfluidic models with fixed dimensions and rectangular cross‐section microchannels. Here, a Cayley‐tree pattern, fabricated using lithography‐less, fluid shaping technique in a modified Hele‐Shaw cell is used to emulate the brain vasculature in a microfluidic chip. This geometry generates an inherent distribution of heterogeneous FSS, due to smooth variations in branch height and width. hCMEC/D3 endothelial cells cultured in the Cayley‐tree designed chip generate a 3D monolayer of brain endothelium with branching hierarchy, enabling the study of the effect of heterogeneous FSS on the brain endothelium. The model is employed to study neuroinflammatory conditions by stimulating the brain endothelium with tumor necrosis factor‐α under heterogeneous FSS conditions. The model has immense potential for studies involving drug transport across the BBB, which can be misrepresented in fixed dimension models.

show abstract

Adenosine A2A receptor agonist ameliorates EAE and correlates with Th1 cytokine‐induced blood brain barrier dysfunction via suppression of MLCK signaling pathway

Liu

Alahiri

Ulloa

et al. 2017

Immunity Inflam & Disease

View full text Add to dashboard Cite

IntroductionMultiple sclerosis (MS) disease activity is associated with blood‐brain barrier (BBB) disruption, which is mediated by inflammatory cytokines released by CD4+ lymphocytes. To assess the effects of adenosine A2A receptors on BBB permeability in vitro and in vivo.MethodsA2A receptor expression was detected by immunostaining in experimental autoimmune encephalomyelitis (EAE) C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein (MOG)35–55, and human MS brain. F‐actin and the tight junction protein Claudin‐5 were assessed in endothelial cells treated with an A2A receptor specific agonist (CGS‐21680) after Th1 cytokine stimulation. EAE mice were divided into control and CGS‐21680 (50 µg/kg, i.p., daily) groups. Disease scores were recorded daily to evaluate neurological impairment. The effects of A2A receptor on inflammation and demyelination were assessed after euthanasia by immunostaining or histology; BBB permeability was measured by sodium fluoride (Na‐F) and FITC‐dextran amounts.ResultsEndothelial A2A receptor was detected in demyelination areas of MS brain samples. In EAE lesions, A2A receptor was expressed in the endothelium in association with immune cell infiltration. Treatment with CGS‐21680 counteracted the effects of Th1 cytokines on endothelial cells in vitro, preventing the reduction of tight junction protein expression and stress fiber formation. The effects of A2A receptor activation were correlated with MLCK phosphorylation signaling repression. In EAE, A2A receptor agonist decreased BBB permeability and inhibited EAE neurologic deficiency in mice.ConclusionsA2A receptor activation at EAE onset helps reduce the effects of Th1 stimulation on BBB permeability, indicating that A2A receptor mediates BBB function in CNS demyelinated disease.

show abstract

Critical role of actin in modulating BBB permeability

Cited by 112 publications

References 64 publications

Quantitative Proteomics Reveals β2 Integrin-mediated Cytoskeletal Rearrangement in Vascular Endothelial Growth Factor (VEGF)-induced Retinal Vascular Hyperpermeability

Quantitative Proteomics Reveals β2 Integrin-mediated Cytoskeletal Rearrangement in Vascular Endothelial Growth Factor (VEGF)-induced Retinal Vascular Hyperpermeability

Bio‐Mimicking Brain Vasculature to Investigate the Role of Heterogeneous Shear Stress in Regulating Barrier Integrity

Adenosine A2A receptor agonist ameliorates EAE and correlates with Th1 cytokine‐induced blood brain barrier dysfunction via suppression of MLCK signaling pathway

Contact Info

Product

Resources

About