Brain arteriovenous malformations (BAVMs) are often incidentally discovered but portend a poor prognosis due to the risk of intracerebral hemorrhage. The primary treatment option ? surgical resection ? is limited by a poor understanding of disease pathogenesis and is sometimes only employed after hemorrhage has occurred due to surgical risks. Development of new treatment strategies requires a more thorough understanding of the scientific underpinnings of BAVM formation. My mentor's laboratory has previously shown that alterations in signaling of constitutively active Notch4 (Notch4*) in endothelial cells throughout the mouse body early in development induces arteriovenous (AV) shunts. Precise regulation of Notch4* signaling is necessary for proper AV specification, and increased Notch4* expression induces AVM formation by driving arterial vascular patterning. These results involved Notch4* expression throughout the body and not only in brain endothelial cells (ECs), but the majority of sporadic AVMs in humans do not involve other organ systems. Thus, a new model is needed that more accurately represents human sporadic BAVM pathophysiology. My long- term goal as a future neurosurgeon-scientist is to develop novel, noninvasive BAVM therapies that can reverse the abnormal arteriovenous programming seen in these AV shunts. In order to do this, however, my immediate objective is to establish a novel BAVM model. My overall hypothesis is that expression of Notch4* specifically in brain ECs leads to AVMs without systemic hemodynamic forces through an Ephrin-B2- dependent mechanism. I will first characterize this BAVM mouse model which induces Notch4* expression specifically in brain ECs. This model utilizes a tamoxifen-inducible Cre to drive expression of Notch4* in brain ECs. I will use advanced in vivo imaging modalities to fully characterize this model and determine whether Notch4* causes enlarged vessel diameter and increased blood flow, and whether AV connections arise out of capillary-sized vessels. I will also investigate how mediators of AV processing, including Ephrin-B2, are involved in the mechanism by which Notch4* induces BAVM formation. The success of this work will help advance our understanding of BAVM pathogenesis by determining whether the BAVMs induced by Notch4* expression are independent of systemic blood pressure and blood flow variability that may occur when Notch4* is expressed in ECs throughout the body. This work would also be the first to define the mechanism mediated by ephrinB2 in Notch4*-induced BAVM formation. We expect this will not only further elucidate the mechanisms underlying BAVM formation but will also help to confirm targets for therapies to prevent the formation and thus the hemorrhagic complications of BAVMs. We also hope our approach of using complex and cutting-edge transgenic mouse models with innovative, in vivo imaging can be applied to other cardiovascular diseases in the future.
Brain arteriovenous malformations (BAVMs) are rare lesions but portend a poor prognosis due to the high morbidity associated with their hemorrhage. Emerging research in both mouse and human tissue has demonstrated a role for signaling of constitutively active Notch4 (Notch4*) in BAVM pathogenesis, but prior mouse models have been confounded by systemic hemodynamic effects caused by the expression of Notch4* throughout the body. This work will characterize a novel murine model in which transgenic Notch4* is expressed specifically in brain endothelial cells in order to more accurately characterize the role that Notch4* plays in BAVM pathogenesis and to investigate how arteriovenous molecular programming mediates Notch4*- induced BAVM formation.
