# Role of Smooth Muscle Progenitor Cells in Obliterative Vascular Remodeling and PH

> **NIH NIH R00** · UNIVERSITY OF ARIZONA · 2020 · $249,000

## Abstract

Pulmonary hypertension (PH) is characterized by obliterative pulmonary vascular remodeling and progressive
elevation of pulmonary vascular resistance that leads to right heart failure and eventual death. Although great efforts
have been made with known treatment of PH, current therapies fail to reverse the disease and mortality remains high.
Better understanding of the pathogenesis of PH is warranty to identify druggable targets for PH patients. Accumulation
of smooth muscle cell (SMC) in the intima and media of pulmonary arterial lesion is the hallmark of obliterative
pulmonary vascular remodeling. However, the underlying mechanisms remain elusive. Recently, the PI’s previous
studies identified a first mouse model of PH [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 PH
including idiopathic PAH. Using this model, a subpopulation of smooth muscle progenitor cells expressing CD133 (a
marker of progenitor cells) and α-smooth muscle actin (α-SMA) (CD133+ SMPCs) was identified. This population of
progenitor cells was enriched at the occlusive vascular lesions as well as the plexiform-like lesions and muscularized
pulmonary arterioles. These cells expressed high levels of the proliferation-specific transcription factor Forkhead Box
M1 (FoxM1), indicating their highly proliferative potential. Genetic depletion of CD133+ cell population inhibited chronic
hypoxia-induced PH. Decreased PH phenotype in another novel mouse model with tamoxifen-inducible deletion of
Foxm1 in smooth muscle cells (SMMHC-CreERT2;Foxm1f/f) was also observed. CXCL12 derived from endothelial cells
(EC) regulated SMC proliferation and FOXM1 induction. Thus, the proposal hypothesis is that pulmonary vascular ECs
and SMPCs cross-talk via CXCL12/CXCR4/FOXM1 signaling plays a fundamental role in mediating obliterative vascular
remodeling and thereby severe PH. The proposed studies will address the following Specific Aims. In Aim 1, this study
will define the role of the newly identified CD133+ SMPCs in the pathogenesis of obliterative vascular remodeling and
severe PH. In Aim 2, this study will address the role of FoxM1 expressed in SMPCs in oblibterative vascular remodeling
and severe PH and explore the translational potential of targeting FoxM1. In Aim 3, this study will delineate the integrated
signaling responsible for obliterative pulmonary vascular remodeling in CD133+ SMPCs activated by ECs. Completion
of these proposed studies will 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 PH in patients.

## Key facts

- **NIH application ID:** 10001625
- **Project number:** 5R00HL138278-04
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Zhiyu Dai
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001625

## Citation

> US National Institutes of Health, RePORTER application 10001625, Role of Smooth Muscle Progenitor Cells in Obliterative Vascular Remodeling and PH (5R00HL138278-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10001625. Licensed CC0.

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