Interruption of vascular endothelial growth factor receptor 2 signaling induces a proliferative pulmonary vasculopathy a
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ORIGINAL CONTRIBUTION
Interruption of vascular endothelial growth factor receptor 2 signaling induces a proliferative pulmonary vasculopathy and pulmonary hypertension Max‑Paul Winter1 · Smriti Sharma1 · Johanna Altmann1 · Veronika Seidl1 · Adelheid Panzenböck1 · Arman Alimohammadi1 · Thomas Zelniker1 · Bassam Redwan2 · Felix Nagel3 · David Santer3 · Alexander Stieglbauer5 · Bruno Podesser3 · Maria Sibilia4 · Thomas Helbich5 · Gerald Prager6 · Aysegül Ilhan‑Mutlu6 · Matthias Preusser6 · Irene M. Lang1 Received: 18 November 2019 / Accepted: 16 July 2020 © The Author(s) 2020
Abstract Pulmonary 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. Keyword Pulmonary hypertension · VEGFR-2 · FLK · Kdr · Murine model
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00395-020-0811-5) contains supplementary material, which is available to authorized users. * Irene M. Lang [email protected] 1
Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18‑20, 1090 Vienna, Austria
2
Division of Thoracic Surgery and Lung Transplantation, Department of Cardiothoracic Surgery, University Hospital of Münster, Münster, Germany
3
Ludwig Boltzmann Cluster for Cardiovascular Research, Center of Biomedical Research, Vienna, Austria
Abbreviations CO Cardiac output EC
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