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A2107 - Inhibition of mTORC2 Upregulates PDGFRs Expression and Contributes to the Development of Pulmonary Hypertension
Author Block: H. Tang1, K. Wu1, Y. Gu1, J. Wang1, A. Makino2, J. X. Yuan1; 1Department of Medicine, University of Arizona, Tucson, AZ, United States, 2Department of Physiology, University of Arizona, Tucson, AZ, United States.
Rationale: Concentric pulmonary arterial wall thickening due to enhanced pulmonary arterial smooth muscle cell (PASMC) proliferation is a major cause for the elevation of pulmonary vascular resistance and pulmonary arterial pressure in patients with idiopathic pulmonary arterial hypertension (IPAH). mTOR, a serine-threonine kinase functionally involved in two distinct protein complexes namely mTORC1 and mTORC2, has been shown to regulate vascular smooth muscle cell proliferation and apoptosis. This study aims to investigate whether complexities in PASMC play differential functions in the development and progression of pulmonary hypertension (PH). Methods: All experiments were approved by the Ethics/Animal Care Committee at the University of Arizona. We generated inducible and smooth muscle cell conditional gene knockout mice of mTOR, Raptor, and Rictor by crossbreeding floxed mice with SMMHC-CreERT2 mice. Following tamoxifen injections, knockout (KO) mice and wild type (WT) control mice were exposed to normoxia or hypoxia (10% FiO2) and right ventricle systolic pressure (RVSP) were measured to evaluate pulmonary hypertensive changes. The pulmonary artery (PA) pressure were measured using the isolated perfused/ventilated lung system to determine acute hypoxia induced pulmonary vasoconstriction in mice. Lungs, PA tissues and PASMC were isolated from WT and KO mice for molecular and cellular experiments. Results: We reports that deletion of mTOR or Raptor in vascular smooth muscle cells significantly attenuated the development of PH. However, deletion of Rictor in smooth muscle cells results in spontaneous mild pulmonary hypertension under normoxic conditions and negligibly affects the development of hypoxia-induced pulmonary hypertension. A series of experiments demonstrated that the both platelet-derived growth factors α and β (PDGFRs) are upregulated in PASMC isolated from Rictor KO mice. In vitro, inhibition of mTORC2 function, but not mTORC1, actually upregulated PDGFRs, and contributed to the cell proliferation and migration in PASMC. Conclusion: In these studies, we found that SM-specific KO of Rictor actually upregulated PDGF receptors α and β, which partially compromises the therapeutic effect of mTORC2 inhibition on experimental PH. These data suggest that mTOR, along with Raptor (via mTORC1) and Rictor (via mTORC2), are all crucial for the development of PH. Pharmacologically targeting on mTOR or mTORC1 and mTORC2 may be an effective therapeutic intervention for pulmonary hypertension. The inhibitors of mTOR, or mTORC1 and mTORC2, should be jointly used with inhibitors of PDGF receptors to treat patients with pulmonary arterial hypertension because of the upregulated PDGFRα and PDGFRβ in PASMC.