# Function and Regulation of MEIS1 in Vascular Disease

> **NIH NIH K99** · AUGUSTA UNIVERSITY · 2023 · $113,520

## Abstract

PROJECT SUMMARY
Vascular smooth muscle cells (VSMCs), the major cell type of medium- and large-sized arteries, undergo
phenotypic switching in vascular diseases such as post-angioplasty restenosis and atherosclerosis.
Understanding the key players that promote VSMC plasticity will inform targeting strategies for downstream
signaling pathways and nuclear events effecting pathological changes in gene expression. Myocardin (MYOCD)
is a potent transcriptional coactivator of the VSMC differentiated state and loss of expression portends vascular
pathology. Despite the hundreds of papers describing MYOCD expression and activity in various contexts, its
transcriptional regulation in vivo is virtually unknown. I have discovered a binding site for Myeloid Ecotropic Viral
Integration Site 1 (MEIS1), a previously unrecognized transcription factor in VSMCs, in the 5’ promoter region of
Myocd, and preliminary studies show MEIS1 binding and transactivation of the Myocd gene. MEIS1 is reduced
in human VSMCs of atherosclerotic coronary arteries and transcriptomic profiling from Biobank of Karolinska
Endoarterctomy (BiKE) showed significant down-regulation of MEIS1 in plaques versus normal arteries as well
as in symptomatic versus asymptomatic patients. To date, there has been only one report of MEIS1 in VSMCs
and nothing known beyond descriptive findings in pulmonary hypertension. Previous Meis1 loss-of-function and
protein expression studies have been difficult to interpret because of the lack of a true null mouse model and
faulty commercial antibodies. Preliminary studies below show an increased proliferation and migration of VSMCs
with loss of Meis1 function; gain-of-function studies reveal the maintenance of the contractile state. I have
generated a versatile mouse model representing the first true null Meis1 allele and its detection at the protein
level. An important component of my studies will be the utilization of a new VSMC-restricted Cre driver I have
helped characterize (Itga8-CRERT2) for more refined in vivo loss-of-function studies. Additional studies support
multiple enhancers that drive VSMC expression of Meis1. Collectively, the preliminary work support my
hypothesis that MEIS1 is a VSMC enriched transcription factor that promotes VSMC differentiation via
transactivation of Myocd. I propose to test this hypothesis in three aims over the course of this K99/R00 award.
The K99 Aim 1 will elucidate the VSMC phenotype with loss of endogenous MEIS1. R00 Aim 2 will elucidate the
transcriptional regulation of Myocd in vivo through an evolutionarily-conserved MEIS1-response element using
state-of-the-art genome editing in mice. R00 Aim 3 will elucidate the functional cis-regulome of MEIS1 in vascular
disease. Completion of the proposed studies will provide new insight into the contribution of MEIS1 to VSMC
differentiation and vascular homeostasis and the mechanistic regulation of Meis1 in vascular diseases.
Conceptual and experimental training related to m...

## Key facts

- **NIH application ID:** 10723084
- **Project number:** 1K99HL169827-01
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Amr Salem
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $113,520
- **Award type:** 1
- **Project period:** 2023-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10723084

## Citation

> US National Institutes of Health, RePORTER application 10723084, Function and Regulation of MEIS1 in Vascular Disease (1K99HL169827-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10723084. Licensed CC0.

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