ArticleActa neuropathologica2015
Soluble VCAM-1 impairs human brain endothelial barrier integrity via integrin α-4-transduced outside-in signalling.
Article in Acta neuropathologica, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 84 citations in OpenAlex.
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- VCAM-1 in Cognitive Impairment: Mechanisms, Biomarker Potential, and Therapeutic Targeting.Aging and disease · 2025Review
- Recent advances of engineering cell membranes for nanomedicine delivery across the blood-brain barrier.Journal of nanobiotechnology · 2025Review
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- Molecular Mechanisms Underlying Amyloid Beta Peptide Mediated Upregulation of Vascular Cell Adhesion Molecule-1 in Alzheimer Disease.The Journal of pharmacology and experimental therapeutics · 2024Article
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- Neuroinflammation, cerebrovascular dysfunction and diurnal cortisol biomarkers in a memory clinic cohort: Findings from the Co-STAR study.Translational psychiatry · 2024Article
- Role of fenofibrate in multiple sclerosis.European journal of medical research · 2024Review
- Peripheral blood BDNF and soluble CAM proteins as possible markers of prolonged disorders of consciousness: a pilot study.Scientific reports · 2024Article
- Advancements in strategies for overcoming the blood-brain barrier to deliver brain-targeted drugs.Frontiers in aging neuroscience · 2024Review
- Barriers of the CNS transfer rate dynamics in patients with vascular cognitive impairment and dementia.Frontiers in aging neuroscience · 2024Article
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Human brain microvascular endothelial cells forming the blood-brain barrier (BBB) release soluble vascular cell adhesion molecule-1 (sVCAM-1) under inflammatory conditions. Furthermore, sVCAM-1 serum levels in untreated patients with multiple sclerosis (MS) correlate with a breakdown of the BBB as measured by gadolinium-enhanced MRI. To date, it is unknown whether sVCAM-1 itself modulates BBB permeability. Here, we provide evidence that human brain endothelium expresses integrin α-4/β-1, the molecular binding partner of sVCAM-1, and that sVCAM-1 directly impairs BBB function by inducing intracellular signalling events through integrin α-4. Primary human brain microvascular endothelial cells showed low to moderate integrin α-4 and strong β-1 but no definite β-7 expression in vitro and in situ. Increased brain endothelial integrin α-4 expression was observed in active MS lesions in situ and after angiogenic stimulation in vitro. Exposure of cultured primary brain endothelial cells to recombinant sVCAM-1 significantly increased their permeability to the soluble tracer dextran, which was paralleled by formation of actin stress fibres and reduced staining of tight junction-associated molecules. Soluble VCAM-1 was also found to activate Rho GTPase and p38 MAP kinase. Chemical inhibition of these signalling pathways partially prevented sVCAM-1-induced changes of tight junction arrangement. Importantly, natalizumab, a neutralising recombinant monoclonal antibody against integrin α-4 approved for the treatment of patients with relapsing-remitting MS, partially antagonised the barrier-disturbing effect of sVCAM-1. In summary, we newly characterised sVCAM-1 as a compromising factor of brain endothelial barrier function that may be partially blocked by the MS therapeutic natalizumab.
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