Modulation of miR-23b Wnt/β-catenin Axis Strengthens Endothelial Barrier Properties.

Authors

Victor Anthony Martinez, Rose E Presby, Sara Nakanishi, Pallavi Gaur, Ugur Akcan, Johannes Daugaard Krog, Iben Daugaard Krog, Lipi Das, David S Johnson, Danny Jamoul, Douglas Jury, Brian Lawson, Jacob Körbelin, Lewis M Brown, Vilas Menon, Dritan Agalliu, Irene Munk Pedersen

Published in

Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e18421. Jul 30, 2026. Epub Jul 30, 2026.

Abstract

Blood-brain barrier (BBB) disruption drives stroke and other CNS disorders pathology, yet restoring its integrity remains challenging. Using an unbiased anti-miR lentiviral screen, miR-23b was identified as a critical negative regulator of BBB integrity in brain endothelial cells (BECs). Targeted inhibition of miR-23b using anti-miR-23b, validated by Wnt-reporter, Wnt-rescue, and eCLIP analysis, demonstrates that BEC miR-23b silencing, enhances junctional protein expression and strengthens barrier function while suppressing transcellular transport. Global multi-omics analysis reveals that miR-23b acts as a robust driver of angiogenesis-specific genes and proteins. Conversely, anti-miR-23b induces the expression of factors essential for BBB stabilization and repair. Notably, anti-miR-23b enhances these protective barrier properties through a multi-faceted regulation of Wnt/β-catenin, TGF-β, Notch, and VEGF signaling mechanisms. Using a 3D microfluidic platform, anti-miR-23b was shown to foster BBB repair by accelerating vessel maturation and enhancing resilience against ischemic injury. Proof-of-concept studies show that BEC-specific AAVBR1-anti-miR-23b gene therapy reinforces BBB tight junctions, reduces BBB leakage, and improves outcome measures in a transient middle cerebral artery occlusion (t-MCAO) stroke model. Thus, miR-23b is a critical regulator of cerebrovascular integrity, positioning anti-miR-23b as a promising RNA-based therapy to enhance BBB stability and repair in stroke and other CNS disorders.

PMID:
42531597
Bibliographic data and abstract were imported from PubMed on 31 Jul 2026.

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