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 ?-smooth muscle actin (?-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.
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, the proposal study is trying to identify what factors are responsible for pulmonary hypertension. So, completion of this study can help to develop new effective therapeutic strategy for treatment of this devastating disease.
