# Cholesterol Regulation of Endothelial K+ Channels

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2023 · $41,286

## Abstract

Kir2.1 is a major potassium channel in endothelial cells (ECs), which has a pivotal role in the cellular
response to hemodynamic flow stimuli by regulating flow-induced activation of the Akt1 signaling
pathway. We have recently established that flow-activation of Kir channels critically depends on the
endothelial glycocalyx. Furthermore, we showed that an enriched high fat-diet (HFD) resolves into
dyslipidemia, which results in shortening the length and stiffening of endothelial glycocalyx. These
changes in the glycocalyx are damaging because they abrogate flow-induced activation of Kir2.1.
Victor’s studies focus on elucidating the mechanisms of HFD-induced stiffening of the EC cortical
envelope which we showed critically depends on scavenger receptor for uptake of lipids, Cd36. In
Aim 1 of this project, Victor proposes that endothelial Cd36 also plays a major role in HFD-induced
stiffening and shortening of the endothelial glycocalyx. This hypothesis is addressed by assessing the
biomechanical properties and the length of the glycocalyx using Atomic Force Microscopy (AFM) on
ECs exposed to pro-atherogenic oxLDL in vitro and on intact aortas of HFD-fed mice. The role of
Cd36 will be determined via loss-of-function models employing an in vitro genetic expression
knockdown in ECs, and a novel in vivo inducible EC-specific transgenic mouse knockdown generated
in our laboratory. The knockdown of Cd36 is observed to prevent HFD-induced EC stiffening of the
cortical envelope and we expect that it will also prevent EC stiffening and shortening of the
endothelial glycocalyx. It is also well established that Akt1 activation plays an important role in flow-
induced cytoskeleton remodeling and maintenance of the endothelial barrier. Since we found earlier
that flow-induced Akt1 activation requires Kir2.1 activity, in Aim 2 of this project, Victor proposes that
endothelial Kir2.1 may also play a role in the maintenance of endothelial biomechanical properties and
the integrity of the barrier. This hypothesis is addressed through assessment of both biomechanical
properties (via AFM) and barrier integrity (via electrical resistance measurement) in EC layers with a
genetic deletion of Kir2.1. Our laboratory will also utilize a published in vivo inducible EC-specific
transgenic mouse knockdown to analyze biomechanical properties (via AFM) and barrier integrity (via
high resolution confocal microscopy) of intact aortas. Knockdown of Kir2.1 is observed to disrupt flow-
induced activation of Akt1 and we expect that this will result in disruption of the endothelial barrier and
the biomechanical properties of ECs.

## Key facts

- **NIH application ID:** 10694538
- **Project number:** 3R01HL073965-15S1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Irena Levitan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $41,286
- **Award type:** 3
- **Project period:** 2022-12-06 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10694538

## Citation

> US National Institutes of Health, RePORTER application 10694538, Cholesterol Regulation of Endothelial K+ Channels (3R01HL073965-15S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10694538. Licensed CC0.

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