TGF-β2 Inhibition Ameliorates Pulmonary Arterial Hypertension through Suppressing Endothelial-mesenchymal Transition

Pulmonary artery hypertension (PAH) is a global health problem affecting all age groups, particularly in the elderly population. The yearly treatment cost for each PAH patient in the USA is 80,000 US$ (https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(18)30268-6/fulltext), which brings enormous economic burden to both patients and the community.Irreversible and sustained vascular remodeling is one of the major features of PAH progression. Consequently, most of the PAH-targeted drugs, mostly vasodilators that benefit only mild to moderate PAH patients (phase I-II), but not more severe (phase III-IV) PAH patients with advanced vascular remodeling. An in-depth understanding of the process of pulmonary vascular remodeling is essential for developing more effective therapeutic strategies against PAH.The mutation of bone morphogenetic protein type 2 receptor (BMPR2) accounts for ~80% of hereditary PAH. The loss of BMPR2 function in human pulmonary artery endothelial cells (HPAECs) increased the expression of α-smooth muscle actin and smooth muscle protein 22α, the main markers of endothelial-mesenchymal transition (EndMT) involved in the pathogenesis of PAH. Transforming growth factor β (TGF-β) plays crucial roles in regulating EndMT and vascular remodeling in BMPR2 mutation. Blocking TGF-β signaling with pan-TGF-β antibodies or TGF-β ligand trap reduce right ventricular systolic pressure in monocrotaline-induced PAH rats and hypoxia-induced PAH mice. However, most of the previous studies mainly focused on TGF-β1, the roles of TGF-β2 and TGF-β3 in vascular remodeling and PAH development are still unclear.In this proposal, we re-analyze a previously published transcriptome data of human PAH lung tissue from the GEO dataset (GSE117261) and identified TGFB2 and TGFB3, but not TGFB1 were increased in lung samples of PAH patients. Mutation of BMPR2 exon 2 in HPAECs increased expressions of TGFB2 and TGFB3, but not TGFB1. Moreover, two SNP sites near TGFB2 are associated with chronic obstructive pulmonary disease, one of the major causes of PAH. Our preliminary results show TGFβ2 is more potent than TGF-β1 in inducing Smad3 activation and expression of EndMT-related genes in HPAECs. Based on these promising observations, we hypothesize that endothelial TGF-β2 plays an active part in pulmonary vascular remodeling and PAH progression through inducing EndMT.This study shall provide the first line of evidence demonstrating a significant role of endothelial TGF-β2 activation in the pathogenesis of PAH. The identification of key TGF-β signaling mediator(s) shall help better understanding of the association between TGF-β2 and EndMT. We will also explore the therapeutic potential of pharmacological inhibition of TGF-β2 in the treatment of PAH. ( 400 words limit)