# MiR-204 regulates type 1 IP3R/Ca2+ axis to control vascular smooth muscle cell contractility and blood pressure: Potential role of the gut microbiome

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2020 · $456,447

## Abstract

Project Summary
Hypertension is the most prevalent cardiovascular disorder worldwide. Deregulation of vascular
smooth muscle cell (VSMC) contraction is a final common pathway in hypertension. Intracellular
calcium (Ca2+) is a trigger and key determinant of VSMC contraction. Vascular smooth muscle
cytosolic Ca2+ concentration is tightly regulated by Ca2+ influx and efflux from the extracellular
space and from intracellular stores, most notably the sarcoplasmic reticulum. Inositol 1,4,5-
trisphosphate (IP3) through its receptors (IP3R) controls Ca2+ release form the sarcoplasmic
reticulum into the cytoplasm.
Hypertension is a multi-system disease. Disruption of homeostatic mechanisms in distant
organs can affect vascular tone. As one example, bacteria that inhabit the gut (gut microbiome)
can modulate blood pressure. Normotensive animals become hypertensive when transplanted
with gut microbiota from hypertensive animals, and vice versa. Furthermore, hypertension in
humans is associated with specific alterations in gut microbial diversity, lending credence to the
premise that a change in gut microbial load and diversity (dysbiosis) contributes to the
pathogenesis of hypertension. Our preliminary data shows that dysbiosis in mice caused by
broad-spectrum antibiotics leads to hypercontractility of blood vessels and associated
upregulation of IP3R1. In addition, we have evidence that broad-spectrum antibiotics
downregulate expression of miR-204, a microbiome-sensitive microRNA, in vascular smooth
muscle cells. Moreover, miR-204 targets IP3R1, and mice with global deletion of miR-204 are
susceptible to developing hypertension. We therefore hypothesize that miR-204 is a key
regulator of VSMC contractility, and its downregulation due to gut microbial dysbiosis promotes
hypertension.
This application will examine the role of miR-204 in regulating VSMC Ca2+ and explore the
mechanisms by which it does so. It will use mice with deletion of miR-204 and IP3R1 in VSMC,
and state-of-the-art methodologies to assess Ca2+ flux in cells and in vessels of live animals.
Using these unique tools, and with the assembled expertise, it will determine if miR-204 controls
blood pressure, VSMC Ca2+ homeostasis and VSMC contraction via IP3R1. In addition, it will
blaze a trail connecting the gut microbiome and regulation of vascular tone, by determining if gut
microbial dysbiosis disrupts VSMC Ca2+ homeostasis, and promotes hypertension through
downregulation of miR-204. Information gained from this work will be a vertical advancement in
the field of hypertension research.

## Key facts

- **NIH application ID:** 10291115
- **Project number:** 7R01HL150360-02
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Modar O. Kassan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $456,447
- **Award type:** 7
- **Project period:** 2020-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10291115

## Citation

> US National Institutes of Health, RePORTER application 10291115, MiR-204 regulates type 1 IP3R/Ca2+ axis to control vascular smooth muscle cell contractility and blood pressure: Potential role of the gut microbiome (7R01HL150360-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10291115. Licensed CC0.

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