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VEGFR2 Expression Correlates with Postnatal Development of Brain Arteriovenous Malformations in a Mouse Model of Type I Hereditary Hemorrhagic Telangiectasia
Han, C.; Nguyen, C.L.; Scherschinski, L.; Schriber, T.D.; Arthur, H.M.; Lawton, M.T.; Oh, S.P. VEGFR2 Expression Correlates with Postnatal Development of Brain Arteriovenous Malformations in a Mouse Model of Type I Hereditary Hemorrhagic Telangiectasia. Biomedicines2023, 11, 3153.
Han, C.; Nguyen, C.L.; Scherschinski, L.; Schriber, T.D.; Arthur, H.M.; Lawton, M.T.; Oh, S.P. VEGFR2 Expression Correlates with Postnatal Development of Brain Arteriovenous Malformations in a Mouse Model of Type I Hereditary Hemorrhagic Telangiectasia. Biomedicines 2023, 11, 3153.
Han, C.; Nguyen, C.L.; Scherschinski, L.; Schriber, T.D.; Arthur, H.M.; Lawton, M.T.; Oh, S.P. VEGFR2 Expression Correlates with Postnatal Development of Brain Arteriovenous Malformations in a Mouse Model of Type I Hereditary Hemorrhagic Telangiectasia. Biomedicines2023, 11, 3153.
Han, C.; Nguyen, C.L.; Scherschinski, L.; Schriber, T.D.; Arthur, H.M.; Lawton, M.T.; Oh, S.P. VEGFR2 Expression Correlates with Postnatal Development of Brain Arteriovenous Malformations in a Mouse Model of Type I Hereditary Hemorrhagic Telangiectasia. Biomedicines 2023, 11, 3153.
Abstract
Brain arteriovenous malformations (BAVMs) are a critical concern in hereditary hemorrhagic telangiectasia (HHT) patients, carrying the risk of life-threatening intracranial hemorrhage. While traditionally seen as congenital, the debate continues due to documented de novo cases. Our primary goal was to identify the precise postnatal window in which deletion of the HHT gene Endoglin (Eng) triggers BAVM development. We employed SclCreER(+);Eng2f/2f mice, enabling timed Eng gene deletion in endothelial cells via tamoxifen. Tamoxifen was given at four postnatal periods: P1-3, P8-10, P15-17, and P22-24. BAVM development was assessed at 2-3 months using latex dye perfusion. We examined angiogenic activity by assessing vascular endothelial growth factor receptor 2 (VEGFR2) expression via Western blotting and Flk1-LacZ reporter mice. Longitudinal magnetic resonance angiography (MRA) was conducted up to 9 months. BAVMs emerged in 88% (P1-3), 86% (P8-10), and 55% (P15-17) of cases, with varying localization. Notably, the P22-24 group did not develop BAVMs but exhibited skin AVMs. VEGFR2 expression peaked in the initial 2 postnatal weeks, coinciding with BAVM onset. These findings support the “second hit” theory, highlighting the role of early postnatal angiogenesis, in initiating BAVM development in HHT type I mice.
Biology and Life Sciences, Neuroscience and Neurology
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