TY - JOUR T1 - Formation of typical vascular lesions in a new experimental model of pulmonary arterial hypertension JF - European Respiratory Journal JO - Eur Respir J VL - 42 IS - Suppl 57 SP - P482 AU - Max-Paul Winter AU - Arman Alimohammadi AU - Adelheid Panzenboeck AU - Maria Sibilia AU - Felix Nagel AU - David Santer AU - Bruno Podesser AU - Sherin Alias AU - Maria Frey AU - Irene Lang Y1 - 2013/09/01 UR - http://erj.ersjournals.com/content/42/Suppl_57/P482.abstract N2 - Background:Pulmonary arterial hypertension (PAH) is a progressive disease characterized by obstruction of small pulmonary arteries leading to increased pulmonary vascular resistance. The key pathologic finding is a negative vascular remodeling process with total vessel occlusion and a monoclonal expansion of endothelial cells. Vascular endothelial growth factor (VEGF) signaling plays a significant role in this process. Aim of our study was to investigate whether inhibition of VEGFR-2 (KDR) by gene manipulation may replicate classical pulmonary vasculopathy.Methods:We utilized mice with conditional KDR knock-out in endothelial cells (KDR-/-). KDRflox/flox/Tie-2Cre and KDRflox/flox/Tie-2 mice were injected intraperitoneally with tamoxifen for 3 weeks to induce knock-out. KDR-/- mice and wild type littermates were held in an environmental chamber with FiO2 of 0.1 or under normoxia for 2, 4, and 6 weeks. We investigated the effect of KDR deletion and chronic normobaric hypoxia on pulmonary hemodynamics and right ventricular hypertrophy.Results:KDR-/- mice showed significantly increased right ventricular pressures (RVSP’s) and Fulton indices after 2, 4, and 6 weeks under normoxic conditions, compared with wild type controls. Both KDR-/- and wild type mice showed increased RVSP’s under normobaric hypoxia. KDR-/- mice revealed significantly higher RVSP’s and Fulton indices than controls after 4 and 6 weeks. Lung histologies demonstrated neointimal thickening and vessel occlusions in lungs of KDR-/- mice resembling human pulmonary arteriopathy.ConclusionClassical pulmonary arterial hypertension was induced in C57/BL6J mice by direct ablative gene manipulation of KDR. ER -