End binding-3 inhibitor activates regenerative program in age-related macular degeneration.

Wet age-related macular degeneration (AMD), characterized by leaky neovessels emanating from the choroid, is a main cause of blindness. As current treatments for wet AMD require regular intravitreal injections of anti-vascular endothelial growth factor (VEGF) biologics, there is a need for the development of less invasive treatments. Here, we designed an allosteric inhibitor of end binding-3 (EB3) protein, termed EBIN, which reduces the effects of environmental stresses on endothelial cells by limiting pathological calcium signaling.

Targeting EB3-IPR3 Interface with Cognate Peptide Protects from Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is a lung disease characterized by acute onset of noncardiogenic pulmonary edema, hypoxemia, and respiratory insufficiency. The current treatment for ARDS is mainly supportive in nature, providing a critical need for targeted pharmacological management. We addressed this medical problem by developing a pharmacological treatment for pulmonary vascular leakage, a culprit of alveolar damage and lung inflammation.

IP receptor signaling and endothelial barrier function.

The endothelium, a monolayer of endothelial cells lining vessel walls, maintains tissue-fluid homeostasis by restricting the passage of the plasma proteins and blood cells into the interstitium. The ion Ca, a ubiquitous secondary messenger, initiates signal transduction events in endothelial cells that is critical to control of vascular tone and endothelial permeability. The ion Ca is stored inside the intracellular organelles and released into the cytosol in response to environmental cues.

Microtubule-Associated Protein EB3 Regulates IP3 Receptor Clustering and Ca(2+) Signaling in Endothelial Cells.

The mechanisms by which the microtubule cytoskeleton regulates the permeability of endothelial barrier are not well understood. Here, we demonstrate that microtubule-associated end-binding protein 3 (EB3), a core component of the microtubule plus-end protein complex, binds to inositol 1,4,5-trisphosphate receptors (IP3Rs) through an S/TxIP EB-binding motif. In endothelial cells, α-thrombin, a pro-inflammatory mediator that stimulates phospholipase Cβ, increases the cytosolic Ca(2+) concentration and elicits clustering of IP3R3s.

KIF13B regulates angiogenesis through Golgi to plasma membrane trafficking of VEGFR2.

Although the trafficking of newly synthesized VEGFR2 to the plasma membrane is a key determinant of angiogenesis, the molecular mechanisms of Golgi to plasma membrane trafficking are unknown. Here, we have identified a key role of the kinesin family plus-end molecular motor KIF13B in delivering VEGFR2 cargo from the Golgi to the endothelial cell surface. KIF13B is shown to interact directly with VEGFR2 on microtubules.

VE-cadherin signaling induces EB3 phosphorylation to suppress microtubule growth and assemble adherens junctions.

Vascular endothelial (VE)-cadherin homophilic adhesion controls endothelial barrier permeability through assembly of adherens junctions (AJs). We observed that loss of VE-cadherin-mediated adhesion induced the activation of Src and phospholipase C (PLC)γ2, which mediated Ca(2+) release from endoplasmic reticulum (ER) stores, resulting in activation of calcineurin (CaN), a Ca(2+)-dependent phosphatase. Downregulation of CaN activity induced phosphorylation of serine 162 in end binding (EB) protein 3.

Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke.

Thrombolytic treatment of ischemic stroke with tissue plasminogen activator (tPA) is markedly limited owing to concerns about hemorrhagic complications and the requirement that tPA be administered within 3 h of symptoms. Here we report that tPA activation of latent platelet-derived growth factor-CC (PDGF-CC) may explain these limitations. Intraventricular injection of tPA or active PDGF-CC, in the absence of ischemia, leads to significant increases in cerebrovascular permeability.