Title: Role of Smooth Muscle Progenitor Cells in Obliterative Vascular Remodeling and PH 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, we 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, we identified a subpopulation of smooth muscle progenitor cells expressing CD133 (a marker of progenitor cells) and a-smooth muscle actin (a-SMA) (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 proliferation-specific transcription factor Forkhead Box M1 (FoxM1), indicating their highly proliferative potential. Genetic depletion of CD133+ cell population inhibited chronic hypoxia-induced PH. We also observed decreased PH phenotype in another novel mouse model with tamoxifen-inducible deletion of Foxm1 in smooth muscle cells (SMMHC-CreERT2;Foxm1f/f). We also found that CXCL12 derived from endothelial cells (EC) regulated SMC proliferation and FOXM1 induction. Thus, my 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, we will define the role of the newly identified CD133+ SMPCs in the pathogenesis of obliterative vascular remodeling and severe PH.
In Aim 2, we 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, we will delineate the integrated signaling responsible for obliterative pulmonary vascular remodeling in CD133+ SMPCs activated by ECs. 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 PH in patients.

Public Health Relevance

The proposed research by Dr. Zhiyu Dai is aimed at understanding why some patients develop high blood pressure in the lungs, i.e. pulmonary hypertension. Pulmonary hypertension is a serious and progressive disease that affects 100 million people worldwide. There is currently no cure for the disease with 5-year mortality as great as 50%. In particular, we are trying to identify what factors are responsible for pulmonary hypertension. So, we can help to develop new effective therapeutic strategy for treatment of this devastating disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Career Transition Award (K99)
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NHLBI Mentored Transition to Independence Review Committee (MTI)
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Kalantari, Roya
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Children's Memorial Hospital (Chicago)
United States
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Dai, Zhiyu; Zhu, Maggie M; Peng, Yi et al. (2018) Endothelial and Smooth Muscle Cell Interaction via FoxM1 Signaling Mediates Vascular Remodeling and Pulmonary Hypertension. Am J Respir Crit Care Med 198:788-802
Dai, Zhiyu; Zhu, Maggie M; Peng, Yi et al. (2018) Therapeutic Targeting of Vascular Remodeling and Right Heart Failure in Pulmonary Arterial Hypertension with a HIF-2? Inhibitor. Am J Respir Crit Care Med 198:1423-1434