# Novel Mechanisms Controlling Endothelial Junctions and Vascular Permeability

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2022 · $609,979

## Abstract

Project Summary
The vascular endothelium forms a highly regulated permeability barrier between the blood stream and
interstitial tissues. Excessive vascular leakiness contributes to many inflammation related disease processes,
including edema, sepsis, acute respiratory distress syndrome (ARDS), ischemic stroke, and hemorrhage. To
prevent tissue damage resulting from vascular leakiness during inflammation, there is a need to be able to
enhance endothelial barrier function. Intercellular junctions control changes in endothelial paracellular
permeability, and Vascular-endothelial cadherin (VE-cadherin, CDH5) is a major regulator of endothelial
junctions and paracellular permeability. We will explore a novel hypothesis and approach to understanding its
role in permeability regulation, based on our findings of allosteric regulation of other cadherins at the cell
surface in response to signaling events. The main hypothesis to be examined is that allosteric regulation of VE-
cadherin, in coordination with activities of the actin cytoskeleton, is a key mechanism by which it regulates
endothelial permeability in response to a range of vascular factors. We will use two novel activating
monoclonal antibodies (mAbs) to VE-cadherin that prevent the increase in endothelial permeability induced by
thrombin, VEGF, and TNFa, as major tools to test this hypothesis both in vitro and in vivo and to study the
mechanism of regulation. The specific aims are: A. Determine whether VE-cadherin cell surface regulation is a
common mechanism for a range of endothelial physiological processes. In vitro experiments will be used to
determine whether it is similarly regulated by other key factors, including histamine, angiopoietins, Tie2
receptors, and S1P. Endothelial cells from different microvascular beds will be examined. Collaborative
experiments will be done to determine flow and shear forces affect mAb induced barrier function. We will also
investigate whether activating mAbs inhibit leukocyte diapedesis or affect endothelial morphogenesis and
angiogenesis. B. Elucidate the cellular and biochemical mechanisms underlying VE-cadherin cell surface
regulation. We will investigate the structural and biophysical basis of its activation by mAbs and test the roles
of the phosphorylation of VE-cadherin and associated catenins in activation. We’ll also explore the relationship
between cell surface regulation and endocytosis as well as barrier altering cytoskeletal functions.
C. Investigate whether activation of VE-cadherin by mAbs enhances barrier function in vivo in mice in leaky
vascular conditions or inflammation. We’ll test the effects of activating mAbs on induced acute induced
vascular leak, and leukocyte infiltration. We will also examine their effects on mouse models of inflammatory
disease processes involving the vasculature, including sepsis and Inflammatory Bowel Disease. These studies
will help us understand regulation of endothelial permeability and develop novel appro...

## Key facts

- **NIH application ID:** 10681680
- **Project number:** 7R01HL158982-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** BARRY M. GUMBINER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $609,979
- **Award type:** 7
- **Project period:** 2022-06-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10681680

## Citation

> US National Institutes of Health, RePORTER application 10681680, Novel Mechanisms Controlling Endothelial Junctions and Vascular Permeability (7R01HL158982-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10681680. Licensed CC0.

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