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.

Public Health Relevance

The overall objective of the proposed studies is to determine the role of CD133+ smooth muscle progenitor cells in the mechanisms of obliterative pulmonary vascular remodeling and severe PAH and explore the therapeutic potential of FoxM1 inhibitor in inhibiting PAH in animal models of severe PAH, and thereby provide novel therapeutic approaches for treatment of PAH to reverse pulmonary vascular remodeling and promote survival.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL140409-03
Application #
9939678
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Lin, Sara
Project Start
2018-06-01
Project End
2022-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Children's Memorial Hospital (Chicago)
Department
Type
DUNS #
074438755
City
Chicago
State
IL
Country
United States
Zip Code
60611