Abstract: The present invention concerns an ubiquitin ligase inhibitor for use for preventing and/or treating a disease linked with cerebral hypoperfusion, and an in vitro screening method for the identification of a candidate compound suitable for preventing and/or treating a disease linked with cerebral hypoperfusion.

Abstract: Heart failure with preserved ejection fraction (HFpEF) which results from diastolic dysfunction is a growing epidemiologic problem. However, the pathophysiology of this disease is poorly understood. Our goal is to investigate whether microvessel disease may promote HFpEF. To do so we have used Leptin receptor deficient (Leprdb/db) female mice as a model of HFpEF and performed a transcriptomic analysis via RNA sequencing of the cardiac vascular fraction of both these mice and their control Leprdb/+littermates. In Leprdb/db female mice, end diastolic pressure (EDP) signing diastolic dysfunction is significantly increased from 3 month of age. It is correlated with a cardiac and cardiomayocyte hypertrophy, vascular leakage, endothelial cell activation and leucocyte infiltration. As expected, the RNA sequencing analysis confirmed endothelial dysfunction. Besides, it also revealed a strong increase in several mast cell markers.

Abstract: Thrombosis is the main cause of morbidity and mortality in patients with JAK2V617F positive myeloproliferative neo-plasms (MPN). Recent works reported the presence of JAK2V617F in endothelial cells in some MPN patients. Here, the inventors show that JAK2V617F endothelial cells promote thrombosis through induction of endothelial P-selectin expression and thus demonstrate that P-selectin blockade was sufficient to reduce the increased propensity of thrombosis. Accordingly the present invention relates to a method of treating thrombosis in a patient suffering from a myeloproliferative neoplasm comprising administering to the patient a therapeutically effective amount of a P-selectin antagonist.