# Stromal interaction molecule 1, immune cells, and vascular pathology in established hypertension

> **NIH NIH R01** · EASTERN VIRGINIA MEDICAL SCHOOL · 2021 · $375,000

## Abstract

ABSTRACT — The central mechanisms involved in hypertension-induced vascular pathology, a public
health crisis, remain unknown. There is still a significant rate of adverse events in hypertensive patients
prescribed these therapeutic and 2/3 of hypertensive patients are still resistant to these therapies. Thus,
the critical unmet need is to identify mechanism based-treatable targets to rescue vascular function and
structure in established hypertension. The pilot data showed that transferring healthy Treg into a mouse
with established hypertension-induced by angiotensin II (Ang II) infusion improved vascular endothelial
function and structure. We showed an increase in stromal interaction molecule 1 (STIM1) expression in
Treg that could be responsible for Treg apoptosis by Nox2 and endoplasmic reticulum (ER) stress-
dependent mechanisms. The overexpression of STIM1 in Treg cell caused Treg cell apoptosis. The
depletion of dendritic cells in hypertensive mice improved arterial function and reduced arterial fibrosis and
calcification through a reduction in INFγ and IL-1β release from dendritic cells and the inhibition of the ER
stress in the endothelial cells. The central hypothesis is that STIM1 overexpression in Treg cells, through
ROS and ER stress mechanism, cause Treg cells apoptosis and decrease IL-10 release, which increases
dendritic cell activity leading to an increase in pro-inflammatory cytokines release (INFγ and IL-1β) and a
decrease in anti-inflammatory IL-10 release causing the induction of the ER stress in endothelial cells and
vascular pathology. To advance the Translational Sciences, we will test the hypothesis in two-kidney one-
clip (2K1C) hypertensive mice Ang II-dependent. Specific Aim #1: To determine that in established
hypertension, STIM1 expression is increased in Treg cells causing Treg cells apoptosis, a decrease in IL-10
release, and vascular pathology. Thus disrupting STIM1 expression in Treg cells would restore Treg cells
number, IL-10 levels, and improve vascular endothelial function and reduce fibrosis and calcification in
established hypertension. Specific Aim #2: To delineate that the decrease in IL-10 release, because of
apoptosis in Treg, increases dendritic cells activity to release IFNγ and IL-1β and blunt IL-10 release, which
causes vascular pathology via the induction of the ER stress mechanism in endothelial cells, and therefore
depleting dendritic cells or manipulating the ER stress in endothelial cell improve vascular endothelial
function and reduce fibrosis and calcification in established hypertension-induced by 2K1C. These studies
are central to the mission of the NHLBI and address all Goals and multiple Strategies outlined in the NHLBI
Strategic Plan. These studies will address 1) a need to further illuminate the biological mechanisms and
pathological processes of the contribution of the immune cells, 2) The interaction between the immune
system and the vascular system as a priority research topic and, 3...

## Key facts

- **NIH application ID:** 10206263
- **Project number:** 5R01HL151616-02
- **Recipient organization:** EASTERN VIRGINIA MEDICAL SCHOOL
- **Principal Investigator:** KHALID MATROUGUI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $375,000
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10206263

## Citation

> US National Institutes of Health, RePORTER application 10206263, Stromal interaction molecule 1, immune cells, and vascular pathology in established hypertension (5R01HL151616-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10206263. Licensed CC0.

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