Pulmonary arterial hypertension (PAH) is an incurable disease that is characterized by pulmonary vascular remodeling leading to elevated pulmonary vascular resistance, right ventricular failure and ultimately death. Current therapies can improve symptoms and delay disease progression, but there is no cure. There is a critical need to develop new therapies that effectively halt and reverse the disease by targeting the cellular and molecular mechanisms underlying the pathophysiology of PAH. Our long-term goal is to elucidate pathogenic mechanisms and develop novel curative therapies for PAH.Endothelial progenitor cells (EPCs) have increasingly become implicated in the pathogenesis of PAH. We hypothesize that bone marrow (BM)-derived EPCs undergo a process known as endothelial to hematopoietic transition (EHT), and that EHT-derived macrophages contribute to inflammation in the lung by producing pro-inflammatory cytokines which leads to vascular remodeling. In support of this hypothesis, we have recently shown that EHT occurs in adult animals during the development of pulmonary hypertension and serves as a source of blood progenitors. The primary objective of this proposal is to confirm that EHT plays a critical role in the pathogenesis of PAH and determine the mechanisms that mediate its effect on pulmonary vascular remodeling. To test our hypothesis, we propose to: Aim 1: Determine to what extent EHT occurs during the development of PAH. 1a). Quantify EHT activation in Sugen/hypoxia-induced pulmonary hypertension mouse model by using the inducible VE-cadherin-CreERT2;ZsGreen double transgenic mice. 1b). Determine the potential of CD34+CE133+ EPCs from PAH patients to undergo EHT in vitro. 1c). Determine the potential of EPCs from PAH patients to undergo EHT in vivo. Aim 2: Determine whether inhibition of Runx1 reduces macrophage and pro-inflammatory cytokine levels and alleviates experimental PH. Runx1 inhibition will be achieved (i) in mice by the generation of inducible VE-cadherin-CreERT2;Runx1(fl/fl) mice to delete Runx1 in adult ECs and EPCs, and (ii) in rats by a small molecule Runx1 inhibitor Ro5-3335. Completion of the proposed study will determine if EHT plays an important role in the pathogenesis of PAH, and if EHT inhibition has the potential to serve as a novel therapeutic target for PAH therapy.
|Program type||Transformational Project Award|
|Effective start/end date||07/01/2018 → 06/30/2021|