# Myoendothelial junctions as regulators of endothelial barrier integrity

> **NIH NIH F31** · UNIVERSITY OF VIRGINIA · 2020 · $33,965

## Abstract

ABSTRACT
Septic shock is the leading cause of death in intensive care units and is characterized by severe hypotension
linked with a loss of endothelial cell (EC) barrier function. Current research has focused on the inflammatory
response in post-capillary venules, but not on resistance arteries despite their critical role in blood pressure
regulation. The mechanisms of maintaining barrier function in resistance artery ECs remains unknown and its
elucidation is imperative for understanding the hypotension and reduced barrier function in septic shock.
Resistance arteries, unlike conduit arteries, have holes in their internal elastic lamina, an extracellular matrix that
separates EC and smooth muscle cell (SMC) layers. Within these holes, EC projections form unique signaling
microdomains termed myoendothelial junctions (MEJs). Canonically, MEJs allow for EC-SMC communication
and have been studied for their involvement in regulating vasodilation. However, this proposal presents a novel
function for the MEJ as a structural anchor, based on their “ball and socket” arrangement. We have previously
shown an enrichment of intermediate filaments, structural, and matrix adhesion proteins in the MEJ. Interestingly,
my preliminary data highlight shared features of MEJs with filopodia, which also form cell-cell and cell-matrix
adhesions. Together, these data suggest that the MEJ may be a key component in the maintenance of EC barrier
integrity and therefore a critical regulator in sepsis. The goal of this proposal is to investigate the non-canonical
properties of MEJ structures in maintaining EC adhesion to the arterial wall and thus their contribution to barrier
function. Aim 1 of this proposal will determine the localization of MEJs within individual ECs to establish their
preferential formation at sites more susceptible to barrier dysfunction, i.e. at EC-EC borders, where anchoring to
the arterial wall would reinforce the endothelial barrier. I will use en face (whole mount, blood vessel preparations)
and scanning electron microscopy to compare MEJ localization distribution in mouse resistance arteries. To
determine changes to MEJ formations during sepsis, I will make comparisons of C57Bl/6J mice to a model of
barrier dysfunction using LPS treatments, and also to plasminogen activator inhibitor 1 (PAI-1) knockout mice,
which have reduced MEJ incidence. Aim 2 of this proposal will investigate the importance of extracellular matrix
adhesion proteins, specifically b1 integrin, for MEJ formation and distribution during septic conditions, which
have been shown to participate in filopodia-mediated adhesion. I will utilize novel conditional and inducible mice
to examine total EC deletion versus arterial EC specific deletion of b1 integrin and measure barrier loss following
LPS treatment to assess the role for b1 integrins at the MEJ in barrier dysfunction. Preliminary data demonstrates
an increase in b1 integrin localization to the MEJ following an LPS challenge i...

## Key facts

- **NIH application ID:** 10025174
- **Project number:** 5F31HL149228-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Claire Ruddiman
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $33,965
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10025174

## Citation

> US National Institutes of Health, RePORTER application 10025174, Myoendothelial junctions as regulators of endothelial barrier integrity (5F31HL149228-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10025174. Licensed CC0.

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