Author:
Winter Max-Paul,Sharma Smriti,Altmann Johanna,Seidl Veronika,Panzenböck Adelheid,Alimohammadi Arman,Zelniker Thomas,Redwan Bassam,Nagel Felix,Santer David,Stieglbauer Alexander,Podesser Bruno,Sibilia Maria,Helbich Thomas,Prager Gerald,Ilhan-Mutlu Aysegül,Preusser Matthias,Lang Irene M.
Abstract
AbstractPulmonary arterial hypertension is a severe and progressive disease characterized by a pulmonary vascular remodeling process with expansion of collateral endothelial cells and total vessel occlusion. Endothelial cells are believed to be at the forefront of the disease process. Vascular endothelial growth factor (VEGF) and its tyrosine kinase receptor, VEGF receptor-2 (VEGFR-2), play a central role in angiogenesis, endothelial cell protection, but also in the destabilization of endothelial barrier function. Therefore, we investigated the consequences of altered VEGF signaling in an experimental model, and looked for translational correlates of this observation in patients. We performed an endothelial cell-specific conditional deletion of the kinase insert domain protein receptor (kdr) gene, coding for VEGFR-2, in C57/BL6 mice (Kdr∆end) and held them in an environmental chamber with 10% FiO2 or under normoxia for 6 weeks. Kdr knockout led to a mild PH phenotype under normoxia that worsened under hypoxia. Kdr∆end mice exhibited a significant increase in pulmonary arterial wall thickness, muscularization, and VEGFR-3+ endothelial cells obliterating the pulmonary artery vessel lumen. We observed the same proliferative vasculopathy in our rodent model as seen in patients receiving anti-angiogenic therapy. Serum VEGF-a levels were elevated both in the experimental model and in humans receiving bevacizumab. Interrupted VEGF signaling leads to a pulmonary proliferative arteriopathy in rodents after direct ablative gene manipulation of Kdr. Histologically, similar vascular lesions can be observed in patients receiving anti-VEGF treatment. Our findings illustrate the importance of VEGF signaling for maintenance of pulmonary vascular patency.
Funder
Österreichische Gesellschaft für Kardiologie Open access funding provided by Medical University of Vienna.
Publisher
Springer Science and Business Media LLC
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology
Cited by
29 articles.
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