# Control of Endothelial Mechanotransduction by the Mitochondrial Ca2+ Uniporter: Implications for Atherosclerosis

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2020 · $69,038

## Abstract

PROJECT SUMMARY / ABSTRACT
It is known that local hemodynamic forces modulate the phenotype of vascular endothelial cells (ECs), and this
phenotypic modulation contributes to the focal nature of atherosclerotic disease. ECs in atheroprone arterial
regions, which are exposed to oscillatory shear stress (OS), experience higher levels of reactive oxygen species
(ROS) and exhibit inflammation and increased sensitization to apoptosis compared to ECs in atheroresistant
regions, which are exposed to pulsatile shear stress (PS). Our group made seminal discoveries on the struc-
ture/function of the Mitochondrial Calcium (Ca2+) Uniporter (MCU) complex, an inner mitochondrial membrane
channel responsible for mitochondrial Ca2+ ([Ca2+]m) uptake. It consists of a pore-forming protein, also called
MCU, and auxiliary subunits. MCU expression is regulated by the redox-sensitive transcription factor CREB.
MCU is activated following oxidative modification by mitochondrial ROS (mROS), and persistent activation re-
sults in [Ca2+]m overload and cell death. My lab showed that MCU knockdown inhibits intracellular Ca2+ ([Ca2+]i)
oscillations in cultured ECs exposed to arterial-level steady laminar shear stress (an in vitro analog of PS) sug-
gesting that MCU channel activity ([Ca2+]m uptake) is critical for shear-induced [Ca2+]i signaling and EC function.
For this Supplement, the hypothesis is that aging may regulate both the basal MCU expression/activity and the
MCU expression/activity following EC exposure to either atheroprone (OS) or atheroresistant (PS) flow. Since
senescent ECs have increased ROS levels compared to young ones, it is anticipated that senescent ECs will
express higher MCU basal levels/activity and will demonstrate differential changes in MCU expression/activity
following exposure to OS or PS, compared to young ECs. Specifically, we propose to:
Aim 1: Assess the MCU expression/activity levels in cultured young vs. senescent human umbilical vein ECs
(HUVECs) and human carotid artery ECs (HCtAECs), prior to and following exposure to either atheroprone (OS)
or atheroresistant shear stress (PS).
Aim 2: Characterize the differences in mitochondrial and cell function, prior to and following exposure to OS or
PS, between young and senescent HUVECs and HCtAECs, and assess the role of MCU in those differences.
The effects of MCU knockdown on OS- and PS-induced changes in [Ca2+]m, [Ca2+]i, mROS, cytosolic ROS, and
mitochondrial and EC function will be investigated in senescent vs. young ECs using the same methods as in
the parent R01. By unveiling age-related changes in MCU expression and activity (hence, [Ca2+]m uptake) and
its role in the EC's apoptotic threshold, this work will further advance our understanding of endothelial biology
and may lead to development of drugs that will specifically target senescent ECs in atheroprone arterial regions
and protect them from atherosclerosis.

## Key facts

- **NIH application ID:** 10139830
- **Project number:** 3R01HL142673-03S1
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Barbara Rita Alevriadou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $69,038
- **Award type:** 3
- **Project period:** 2018-08-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10139830

## Citation

> US National Institutes of Health, RePORTER application 10139830, Control of Endothelial Mechanotransduction by the Mitochondrial Ca2+ Uniporter: Implications for Atherosclerosis (3R01HL142673-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10139830. Licensed CC0.

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