Je tiens à exprimer mes sincères remerciements à :Monsieur le Professeur Éric Deutsch, de m'avoir fait l'honneur de présider cette thèse. Monsieur le Professeur Ahmed Idbaih et Monsieur le Professeur Keith Ligon, d'avoir pris le temps de diriger et encadrer cette thèse. Monsieur le Docteur Franck Bourdeaut, Madame la Professeure Magali Svrcek, et Monsieur le Professeur Alex Duval, d'avoir pris le temps de juger ce travail. Monsieur le Docteur Franck Bielle, et Monsieur le Professeur Marc Sanson, pour leur participation à ces travaux. Une partie importante de ces travaux a été réalisée au Dana-Farber Cancer Institute et je tiens à remercier ici très sincèrement mes collègues de Boston pour leur amitié et leurs efforts déterminants dans l'obtention de ces résultats, en particulier Keith Ligon pour son accueil au sein de son laboratoire, ses conseils et ses encouragements.

We investigated (1) EphrinB2 and EphB4 receptor expression in cerebral AVMs, (2) the impact of an altered EphrinB2: EphB4 ratio on brain endothelial cell function and (3) potential translational applications of these data. The following parameters were compared between AVM endothelial cells (AVMECs) and human brain microvascular endothelial cells (HBMVECs): quantified EphrinB2 and EphB4 expression, angiogenic potential, and responses to manipulation of the EphrinB2:EphB4 ratio via pharmacologic stimulation/inhibition. To investigate the clinical relevance of these in vitro data, Ephrin expression was assessed in AVM tissue (by immunohistochemistry) and urine (by ELISA) from pediatric patients with AVM (n = 30), other cerebrovascular disease (n = 14) and control patients (n = 29), and the data were subjected to univariate and multivariate statistical analyses. Compared to HBMVECs, AVMECs demonstrated increased invasion (p = 0.04) and migration (p = 0.08), impaired tube formation (p = 0.06) and increased EphrinB2:EphB4 ratios. Altering the EphrinB2:EphB4 ratio (by increasing EphrinB2 or blocking EphB4) in HBMVECs increased invasion (p = 0.03 and p < 0.05, respectively). EphrinB2 expression was increased in AVM tissue, which correlated with increased urinary EphrinB2 levels in AVM patients. Using the optimal urinary cutoff value (EphrinB2 > 25.7 pg/μg), AVMs were detected with high accuracy (80% vs. controls) and were distinguished from other cerebrovascular disease (75% accuracy). Posttreatment urinary EphrinB2 levels normalized in an index patient. In summary, AVMECs have an EphrinB2:EphB4 ratio that is increased compared to that of normal HBMVECs. Changing this ratio in HBMVECs induces AVMEC-like behavior. EphrinB2 is clinically relevant, and its levels are increased in AVM tissue and patient urine. This work suggests that dysregulation of the EphrinB2:EphB4 signaling cascade and increases in EphrinB2 may play a role in AVM development, with potential utility as a diagnostic and therapeutic target.