Local inhibition of angiogenesis combined with repeated blood clot embolization induces chronic thromboembolic pulmonary hypertension in rabbits

Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe disease characterized by unresolved and organized thrombi obstructing the pulmonary arterial bed, resulting in PH and right ventricular (RV) failure. We previously found that repeated embolization and fibrinolysis inhibition induced CTEPH in rabbits. Neovascularization may play a role in resolving venous thrombi. We hypothesized that inhibition of angiogenesis may prevent clot resolution and promote CTEPH progression. We aimed to investigate whether repeated embolization with blood clots containing an inhibitor of angiogenesis may induce CTEPH in rabbits. Adult male New Zealand rabbits were weekly embolized (x 7) with autologous blood clots containing Sugen, an inhibitor of VEGF receptor, or not. Right heart catheterization was performed 8 weeks after the last embolization. RV function was assessed by transthoracic echocardiography at baseline, after the last embolization and before sacrifice. RV hypertrophy and lung vessel morphometry were analyzed. Repeated embolization with clots containing Sugen resulted in a 44% increase in mean pulmonary arterial pressure, a 2-fold increase in pulmonary vascular resistance index without any change in cardiac output and a 37 % increase in RV diameter compared to baseline; it also induced fibro-thrombotic lesions in large proximal pulmonary arteries and remodeling of distal pulmonary arteries. Embolization with autologous blood clots containing Sugen promoted CTEPH development in rabbits. Obstruction of large proximal pulmonary arteries by fibro-thrombotic lesions highlights the similarity with the human pathology of CTEPH.