# Targeting Smooth Muscle Progenitor Cells for Treatment of Pulmonary Arterial Hypertension

> **NIH NIH R01** · LURIE CHILDREN'S HOSPITAL OF CHICAGO · 2021 · $497,250

## Abstract

Pulmonary arterial hypertension (PAH) is characterized by obliterative pulmonary vascular remodeling and
progressive elevation of pulmonary vascular resistance that leads to right heart failure and premature death.
Although great efforts have been made to treat PAH, current therapies fail to reverse the disease and mortality
remains high. Comprehensive understanding of the mechanisms underlying obliterative pulmonary vascular
remodeling is warranted to identify druggable targets for effective treatment of PAH. Accumulation of smooth
muscle cell (SMC) in the pulmonary vascular lesions is the hallmark of obliterative pulmonary vascular
remodeling. We have recently identified the first mouse model of PAH [Tie2Cre-mediated disruption of Egln1,
encoding hypoxia inducible factor (HIF) prolyl hydroxylase 2 (PHD2), designated Egln1Tie2Cre] with progressive
obliterative vascular remodeling including vascular occlusion and plexiform-like lesion, and right heart failure,
which recapitulates many features of clinical PAH. Using this mouse model as well as the Sugen/Hypoxia rat
model, we identified a subpopulation of smooth muscle progenitor cells expressing CD133 (a marker of
progenitor cells) (CD133+ SMPCs) which were enriched at the occlusive vascular lesions as well as the
plexiform-like lesions and muscularized pulmonary arterioles. These cells expressed high levels of the cell cycle
master regulator Forkhead Box M1 (FoxM1), indicating the highly proliferative potential. Genetic depletion of
CD133+ cell population inhibited chronic hypoxia-induced PH. We also observed decreased vascular remodeling
and PH in mice with tamoxifen-inducible deletion of Foxm1 in smooth muscle cells. Pharmacological inhibition
of FoxM1 attenuated PAH in Sugen/Hypoxia-exposed rats. Thus, we hypothesize that EC-SMPC crosstalk
regulates CD133+ SMPC proliferation in a FoxM1-dependent manner and thereby plays a fundamental role in
the mechanisms of obliterative vascular remodeling and severe PAH. The proposed studies will address the
following Specific Aims. In Aim 1, we will determine the role of smooth muscle progenitor cells in the
mechanisms of pulmonary vascular remodeling and PAH. In Aim 2, we will delineate the molecular mechanisms
of SMPC-mediated vascular remodeling in PAH. In Aim 3, we will explore the translational potential of targeting
FoxM1 for treatment of PAH. We expect that the proposed studies have significant translational potential by
elucidating the fundamental mechanisms of obliterative vascular remodeling and identifying druggable targets
that can pharmacologically reverse obliterative vascular remodeling for the treatment of severe PAH in patients.

## Key facts

- **NIH application ID:** 10189689
- **Project number:** 5R01HL140409-04
- **Recipient organization:** LURIE CHILDREN'S HOSPITAL OF CHICAGO
- **Principal Investigator:** YOU-YANG ZHAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $497,250
- **Award type:** 5
- **Project period:** 2018-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189689

## Citation

> US National Institutes of Health, RePORTER application 10189689, Targeting Smooth Muscle Progenitor Cells for Treatment of Pulmonary Arterial Hypertension (5R01HL140409-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10189689. Licensed CC0.

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