par Martin-Valiente, Edwige
Président du jury Lybaert, Pascale
Promoteur Baeyens, Nicolas
Co-Promoteur Vanhollebeke, Benoît
Publication Non publié, 2024-04-10
Thèse de doctorat
Résumé : Vein of galen aneurysmal malformations (VGAMs) represent congenital arteriovenous fistulas that direct blood flow towards the median vein of the prosencephalon, also known as the vein of Markowski, serving as the embryonic precursor to the vein of Galen. Despite their rarity, VGAMs are the most prevalent type of cerebral arteriovenous shunt observed in neonates and infants, presenting limited therapeutic options. The primary approach for addressing VGAMs is embolization through the trans-arterial route. However, in neonatal cases, endovascular treatment carries a heightened risk profile. Recognizing the limitations of present approaches, uncovering the underlying causes of this disease, and subsequently identifying additional therapeutic strategies is imperative. The urgency arises from the need to fully understand the development of the disease and find treatments that can improve the current therapy methods. Two distinct clinical forms of VGAMs have been recognized: choroidal and mural malformations. VGAMs are associated with a germinal mutation within EPHB4 or RASA1. Interestingly, this high-flow malformation's penetrance is incomplete. Studies have revealed a significant link between the incidence of arteriovenous shunts caused by genetic abnormalities and increased blood flow. In this context, we hypothesized that germline mutation in endothelial cells combined to unique hemodynamics parameters within this vessel are required to develop this malformation.In order to replicate the genetic characteristics of the deformity, we used two approaches to establish a preclinical in vivo model. At first, we caused a decrease in the expression of ephb4a and rasa1a genes in transgenic zebrafish by employing antisense morpholino oligonucleotides. In addition, we created a new line for rasa1a and ephb4a using CRISPR-Cas9 technology. This novel method successfully built a framework that encompasses the genetic foundations of this disease. The zebrafish model, which lacks ephb4a and rasa1a, exhibits similarities in the genetic, hemodynamic, and morphological characteristics seen in patients with VGAMs in the dorsal longitudinal vein of the cerebral vasculature. Simultaneously, we analyzed the specific hemodynamic properties of the zebrafish's dorsal longitudinal vein, which is an analog to the vein of Galen and possesses a distinctive design as a collecting vessel. Upon identifying these factors, we proceeded to explore the importance of blood circulation in the development of these malformations. The research demonstrates a correlation between the development of malformations dues to the incapacity of immature blood vessels to fuse into a collecting vessel in the case of choroidal malformations while defective constriction develops into mural malformations. Endothelial cells play a crucial role in the fusion process and are essential for the appropriate formation of blood vessels. This process is affected by blood flow and is detected and combined by the endothelial cells. The lack of RASA1 significantly disturbs the body's ability to maintain a stable response to blood flow, leading to an uneven activation of MAPK and PI3K signaling pathways influenced by flow. We rectified this imbalance using pharmacological therapies, which not only enhanced the development of the dorsal longitudinal vein but also effectively restored the fusion process in preexisting abnormalities.This thesis provides for the first time a comprehensive cellular explanation of the flow-mediated blood vessel fusion mechanism. Furthermore, our pre-clinical model mimics VGAMs, potentially serving as a valuable tool for identifying innovative and effective therapeutic strategies to treat this malformation and other disorders related to vascular remodeling.

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