Biology subjects

Su, E. J.

Publications and source records attributed to Su, E. J..

4 recordsLinked to original sources

bioRxiv2025

Occludin Acts as a Dynein Adaptor Regulating Permeability and Collateral Angiogenesis

Previous studies of the tight junction protein occludin (OCLN) suggest that multiple phosphorylation sites on the carboxy-terminal domain contribute a regulatory role in vascular barrier properties. However, gene deletion studies failed to identify a clear functional role for OCLN, despite multiple phenotypic alterations. Importantly, previous studies targeting exon 3 allowed expression of a splice variant starting at exon 4, (isoform 4) that expresses the full carboxy-terminal tail. Here we show that the OCLN carboxy-terminus forms a complex with the light intermediate chain (LIC) of dynein to link tight junction cargo to the minus end directed motor protein. Mutational analysis revealed S471 phosphorylation is required for binding to the LIC while S490 phosphorylation is required for trafficking. Expressing OCLN S490A mutant prevented endothelial cell proliferation and collateral angiogenesis. OCLN gene deletion targeting exon 5, preventing full length and isoform 4 expression, resulted in embryonic lethality. In summary, OCLN links tight junction cargo to the dynein motor, regulating trafficking in a phosphorylation dependent manner and contributing to both VEGF-induced vascular permeability and collateral angiogenesis.

cell biology↗

bioRxiv2024

Harnessing micrometer-scale tPA beads for high plasmin flux and accelerated fibrinolysis

Rapid restoration of blood flow is critical in treating acute ischemic stroke. Current fibrinolytic therapies using tissue plasminogen activator (tPA) are limited by low recanalization rates and risks of off-target bleeding. Here, we present a strategy using tPA immobilized on micrometer-scale beads to enhance local plasmin generation. We synthesized tPA-functionalized beads of varying sizes (0.1 m and 1.0 m) and evaluated their efficacy. In vitro assays demonstrated that 1.0 m tPA-beads generated higher plasmin generation compared to free tPA and 0.1 m beads, overcoming antiplasmin inhibition and promoting a self-propagating wave of fibrinolysis. In a murine model of acute ischemic stroke, intravenous administration of 1.0 m tPA-beads at doses nearly two orders of magnitude lower than the standard free tPA dose led to rapid and near-complete thrombus removal within minutes. This approach addresses kinetic and transport limitations of current therapies and may reduce the risk of hemorrhagic complications. TeaserMicrometer-scale tPA beads improve stroke treatment by enhancing local clot-dissolving action.

bioengineering↗

bioRxiv2024

Thrombolysis exacerbates cerebrovascular injury after ischemic stroke via a VEGF-B dependent effect on adipose lipolysis

Cerebrovascular injuries leading to edema and hemorrhage after ischemic stroke are common. The mechanisms underlying these events and how they are connected to known risk factors for poor outcome, like obesity and diabetes, is relatively unknown. Herein we demonstrate that increased adipose tissue lipolysis is a dominating risk factor for the development of a compromised cerebrovasculature in ischemic stroke. Reducing adipose lipolysis by VEGF-B antagonism improved vascular integrity by reducing ectopic cerebrovascular lipid deposition. Thrombolytic therapy in ischemic stroke using tissue plasminogen activator (tPA) leads to increased risk of hemorrhagic complications, substantially limiting the use of thrombolytic therapy. We provide evidence that thrombolysis with tPA promotes adipose tissue lipolysis, leading to a rise in plasma fatty acids and lipid accumulation in the ischemic cerebrovasculature after stroke. VEGF-B blockade improved the efficacy and safety of thrombolysis suggesting the potential use of anti-VEGF-B therapy to extend the therapeutic window for stroke management.

neuroscience↗

bioRxiv2021

Reduced myofibroblast transdifferentiation and fibrotic scarring in ischemic stroke after imatinib treatment

The tyrosine kinase inhibitor imatinib has been reported to improve outcome in patients following ischemic stroke but the exact mechanism remains elusive. Here, utilizing a photothrombotic murine model of middle cerebral artery occlusion (MCAO), we show that imatinib-mediated inhibition of stroke-induced blood-brain barrier (BBB) dysfunction coincided with decreased expression of genes associated with inflammation and fibrosis in the cerebrovasculature. We found that imatinib effectively dampened stroke-induced reactive gliosis and myofibroblast transdifferentiation, whilst having very limited effect on the rest of the glia scar and on peripheral leukocyte infiltration. Further, our data suggest that consolidation of the PDGFR+ portion of the fibrotic scar in imatinib-treated mice contributes to the improvement in functional outcome compared to the vehicle controls, where the PDGFR+ scar is expanding. Comparison with human stroke transcriptome databases revealed significant overlap with imatinib-regulated genes, suggesting imatinib may modulate reactive gliosis and fibrotic scarring also in human stroke.

neuroscience↗