# Transcriptional Regulation by Angiotensin II in Vascular Smooth Muscle Cells

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2022 · $703,887

## Abstract

SUMMARY: Vascular smooth muscle cells (VSMCs) in the blood vessel wall play pivotal roles in cardiovascular
disease (CVD; e.g., hypertension), which affects ~48% of US adults, and which is significantly accelerated by
diabetes (DCVD). When stimulated by factors like diabetes and the growth factor Angiotensin II (AngII), mature
VSMCs de-differentiate through “phenotypic switching” (Phe-sw) via dysregulation of "contractile" and "synthetic”
genes, resulting in increased VSMC proliferation, migration, inflammation, and extracellular matrix (ECM)
production. In the previous funding cycles, we unraveled the first functional roles for AngII-regulated long
noncoding RNAs and (super-)enhancers (a key epigenetic regulatory layer) in VSMCs. Our overall objective in
this renewal is to elucidate the mechanisms regulating diabetes- and AngII-induced VSMC Phe-sw at the
epigenome and single-cell (sc) level and how these mechanisms establish vascular metabolic memory (in which
prior hyperglycemia/AngII exposure leads to persistent long-term DCVD despite subsequent glucose
normalization). We will use state-of-the-art multi-omics and sc-sequencing (seq) approaches to decipher VSMC
behavior in DCVD and metabolic memory and identify new drug targets. Our hypothesis is that diabetic
conditions and AngII coordinately re-program the VSMC transcriptome and epigenome, which lead to persistent
dysregulation of genes promoting Phe-sw to unique cellular states underlying VSMC dysfunction and accelerated
DCVD. This hypothesis is supported by extensive new preliminary data that show: i) a diabetic state augments
AngII actions and promotes VSMC proliferation and Phe-sw gene profiles, which persist even after glucose
normalization; ii) DNA methylation is decreased, and chromatin accessibility is increased at key upregulated
ECM and inflammatory genes in VSMCs from diabetic mice, even after culture in normal glucose; iii) new cell
clusters indicative of Phe-sw occur in aortas of Ang II-infused mice, identified using integrated scRNA- and
scATAC-seq; iv) diabetic stimuli induce 3D chromatin changes in vascular cells, seen using chromatin
conformation assays. We will test our hypothesis in 3 specific aims: 1) Define diabetes-induced transcriptomic
and epigenomic changes [AngII-(in)dependent] in VSMCs at Phe-sw-related genes, and the memory of their
persistent dysregulation after glucose normalization in vitro; 2) Elucidate the de-differentiated VSMC subtypes
and their functions in diabetes- and AngII-induced Phe-sw in arteries, and their persistence after glucose
normalization in vivo, using scRNA-seq and scATAC-seq; and 3) Determine the translational potential for
reversing DCVD and vascular memory by targeting candidate genes/loci mediating diabetes- and AngII-induced
VSMC Phe-sw. This innovative study, using cutting-edge technologies and functional in vivo models, will provide
novel insights into VSMC regulatory networks and epigenetic memory of diabetic vasculopathy. This know...

## Key facts

- **NIH application ID:** 10458055
- **Project number:** 5R01HL106089-11
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Zhen Bouman Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $703,887
- **Award type:** 5
- **Project period:** 2011-01-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10458055

## Citation

> US National Institutes of Health, RePORTER application 10458055, Transcriptional Regulation by Angiotensin II in Vascular Smooth Muscle Cells (5R01HL106089-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10458055. Licensed CC0.

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