Background: Vascular remodelling following venous thrombosis involves vascular endothelial cells, smooth muscle cells and leukocytes and aims to restore vascular patency. Acute pulmonary emboli usually resolve within six months. Yet, in few cases, venous thrombi fail to resolve and transform into fibrous vascular occlusions, resulting in post-thrombotic syndrome or in chronic thromboembolic pulmonary hypertension (CTEPH). The hypothesis of this study was that defective thrombus angiogenesis may contribute to thrombus non-resolution.
Methods and Results: Mice with an endothelial cell-specific deletion of vascular endothelial growth factor receptor 2/ kinase insert domain protein receptor (VEGF-R2/Kdr) were employed in a model of stagnant flow venous thrombosis that is very similar to human deep vein thrombosis.
Biochemical and functional analyses were performed on vascular occlusions from patients with CTEPH, a disease model of non-resolving venous thromboembolism. Endothelial cell-specific deletion of Kdr and subsequent decrease of thrombus vessels delayed thrombus resolution.
Similarly, organized human CTEPH thrombi demonstrated a paucity of vascular structures. Decreased expression of several vessel-specific genes such as KDR, vascular endothelial cadherin and podoplanin were observed in white CTEPH thrombi compared with organizing deep vein thrombi and organizing thrombi from aortic aneurysms. Furthermore, red CTEPH thrombi attenuated the VEGF induced angiogenic response in endothelial cells.
Conclusions: The present work proposes a mechanism of thrombus non-resolution demonstrating that endothelial cell-specific genetic ablation of Kdr impairs thrombus vascularization, misguiding thrombus resolution. Medical conditions associated with the development of CTEPH may be interfering with early thrombus angiogenesis.