title: Defective angiogenesis delays thrombus resolution: a potential pathogenetic mechanism underlying chronic thromboembolic pulmonary hypertension.
abstract: OBJECTIVE
  Restoration of patency is a natural target of vascular remodeling after venous thrombosis that involves vascular endothelial cells and smooth muscle cells, as well as leukocytes. Acute pulmonary emboli usually resolve <6 months. However, in some instances, thrombi transform into fibrous vascular obstructions, resulting in occlusion of the deep veins, or in chronic thromboembolic pulmonary hypertension (CTEPH). We proposed that dysregulated thrombus angiogenesis may contribute to thrombus persistence.
  
  
  RESULTS
  Mice with an endothelial cell-specific conditional deletion of vascular endothelial growth factor receptor 2/kinase insert domain protein receptor were used in a model of stagnant flow venous thrombosis closely resembling human deep vein thrombosis. Biochemical and functional analyses were performed on pulmonary endarterectomy specimens from patients with CTEPH, a human model of nonresolving venous thromboembolism. Endothelial cell-specific deletion of kinase insert domain protein receptor and subsequent ablation of thrombus vascularization delayed thrombus resolution. In accordance with these findings, organized human CTEPH thrombi were largely devoid of vascular structures. Several vessel-specific genes, such as kinase insert domain protein receptor, vascular endothelial cadherin, and podoplanin, were expressed at lower levels in white CTEPH thrombi than in organizing deep vein thrombi and organizing thrombi from aortic aneurysms. In addition, red CTEPH thrombi attenuated the angiogenic response induced by vascular endothelial growth factor.
  
  
  CONCLUSIONS
  In the present work, we propose a mechanism of thrombus nonresolution demonstrating that endothelial cell-specific deletion of kinase insert domain protein receptor abates thrombus vessel formation, misguiding thrombus resolution. Medical conditions associated with the development of CTEPH may be compromising early thrombus angiogenesis.
authors: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors: Sherin
authors: S
authors: Alias
authors: Department of Cardiothoracic Surgery, University Hospital Muenster, Muenster, Germany.
authors: Bassam
authors: B
authors: Redwan
authors: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors: Adelheid
authors: A
authors: Panzenboeck
authors: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors: Max P
authors: MP
authors: Winter
authors: Institute for Biochemistry, Medical School, Justus-Liebig-University, Giessen, Germany.
authors: Uwe
authors: U
authors: Schubert
authors: Department of Lung Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors: Robert
authors: R
authors: Voswinckel
authors: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors: Maria K
authors: MK
authors: Frey
authors: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors: Johannes
authors: J
authors: Jakowitsch
authors: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors: Arman
authors: A
authors: Alimohammadi
authors: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors: Lukas
authors: L
authors: Hobohm
authors: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors: Andreas
authors: A
authors: Mangold
authors: Department of Biomedical Research, Medical University of Vienna, Vienna, Austria.
authors: Helga
authors: H
authors: Bergmeister
authors: Institute for Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors: Maria
authors: M
authors: Sibilia
authors: Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors: Erwin F
authors: EF
authors: Wagner
authors: Department of Thoracic Surgery, Kerckhoff Clinic Heart and Lung Centre, Bad Nauheim, Germany.
authors: Eckhard
authors: E
authors: Mayer
authors: Department of Cardiothoracic Surgery, Medical University of Vienna, Vienna, Austria.
authors: Walter
authors: W
authors: Klepetko
authors: Department of Vascular and Endovascular Surgery, Paracelsus Medical University, Salzburg, Austria.
authors: Thomas J
authors: TJ
authors: Hoelzenbein
authors: Institute for Biochemistry, Medical School, Justus-Liebig-University, Giessen, Germany.
authors: Klaus T
authors: KT
authors: Preissner
authors: Department of Cardiology, Medical University of Vienna, Vienna, Austria.
authors: Irene M
authors: IM
authors: Lang
mesh_terms: D000368:Aged; D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D004195:Disease Models, Animal; D004691:Endarterectomy; D005260:Female; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000601:surgery; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000235:genetics; D013997:Time Factors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000172:deficiency / Q000235:genetics; D054556:Venous Thromboembolism / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000601:surgery; D020246:Venous Thrombosis / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000601:surgery
chemical_list: D042501:Angiogenic Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: endothelium; thrombosis; vascular endothelial growth factor receptor-2