Source: International Congress 2018 – Pathobiology of pulmonary hypertension
Disease area: Interstitial lung diseases, Pulmonary vascular diseases

Abstract

Pulmonary hypertension (PH), an increased blood pressure within the pulmonary vasculature, is a devastating and progressive disease. PH is characterized by increased proliferation of the pulmonary artery smooth muscle cells (PASMC) and subsequent remodeling of the pulmonary arteries. Activation of the ADORA2B receptor on smooth muscle cells has previously been implicated in vascular tissue remodeling. We hypothesize that activation of the ADORA2B receptor in PASMC mediates the development of pulmonary vascular remodeling. We evaluated the development of pulmonary vascular remodeling in two distinct mouse models. We used mice that have ADORA2B conditionally deleted from smooth muscle cells and corresponding controls. Mice were exposed to a combination of SUGEN and hypoxia for 28 days or alternatively, a bi-weekly exposure to bleomycin for 33 days. Additionally, we exposed primary human PASMC to an ADORA2B agonist and evaluated hyaluronan synthase 2 (HAS2) and interleukin-6 (IL-6) expression. Our data demonstrates that conditional deletion of ADORA2B from smooth muscle cells protected the mice against the development of PH features in both mouse models. Remarkably, the mice with conditional deletion of ADORA2B exposed to bleomycin, were not protected against the development of fibrosis. Our in vitro studies using PASMC revealed that activation of the ADORA2B receptor resulted in increased expression of HAS2 and IL-6, both important mediators of vascular remodeling. Taken together, our in vivo and in vitro data indicate that ADORA2B on PASMC mediates the development of pulmonary vascular remodeling. Importantly, these studies also point at ADORA2B as a potential therapeutic target to treat PH.

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T. C. J. Mertens, A. Hanmandlu (ankit.hanmandlu@utexas.edu / Department of Biochemistry and Molecular Biology, M. Medical School, U. , L. Tu (Ly.Tu@inserm.fr / INSERM UMR_S 999, U. Paris-Sud,LE PLESSIS-ROBINSON), C. Phan (phan.carole@gmail.com / INSERM UMR_S 999, U. Paris-Sud,LE PLESSIS-ROBINSON), S. Collum (scott.d.collum@uth.tmc.edu / Department of Biochemistry and Molecular Biology, M. Medical School, U. , N. Chen (ning-yuan.chen@uth.tmc.edu / Department of Biochemistry and Molecular Biology, M. Medical School, U. , J. Davies (jldavies@texaschildrens.org / Department of Pediatrics, B. College of Medicine,Houston), A. Guha (gashrith@houstonmethodist.org / Debakey Heart & Vascular Center, H. Methodist Hospital,Houston), H. Eltzschig (holger.eltzschig@uth.tmc.edu / Department of Anaesthesiology, M. Medical School, U. , M. Blackburn (michael.r.blackburn@uth.tmc.edu / Department of Biochemistry and Molecular Biology, M. Medical School, U. , C. Guignabert (guignabert@gmail.com / INSERM UMR_S 999, U. Paris-Sud,Houston), H. Karmouty-Quintana (harry.karmouty@uth.tmc.edu / Department of Biochemistry and Molecular Biology, M. Medical School, U.. LSC - 2018 - Pulmonary vascular remodeling mediated by ADORA2B in pulmonary artery smooth muscle cells. 3921

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