Doctor of Philosophy (PhD), Ohio University, 2022, Biological Sciences (Arts and Sciences)

The mammalian vasculature caters to tissue specific gaseous exchange and metabolic needs. The brain accounts for the largest consumption of oxygen and glucose, for which a structurally organized and functional cerebrovasculature is essential. Brain arteriovenous malformations (BAVM) are characterized by abnormally enlarged blood vessels, which direct blood through arteriovenous (AV) shunts, bypassing the normal artery-capillary-vein network. High-pressure, low-resistance AV shunts disrupt healthy blood flow and can result in cerebrovascular hemorrhage. BAVM is the leading cause of intracerebral hemorrhage in children, and accounts for 50% of stroke incidences in children and young adults. Clinically, BAVM treatments are invasive and not applicable to all cases; thus, there is critical need to understand BAVM mechanisms and develop targeted therapeutics. Using a mouse model of BAVM, that is deficient in Notch effector Rbpj from endothelial cells, from birth – we show that isolated Rbpj-deficient (RbpjiΔEC) brain endothelial cells (BECs) elicit altered whole-genome transcriptomic profile, early at Postanal day (P)7 when expansion of AV diameters – the most prominent BAVM phenotype is not observed, suggesting contribution of Rbpj regulated effector molecules in triggering onset of BAVM pathogenesis. Cellular studies over the course of characterized developmental time-periods at P7, P10, and P14 revealed that AV expansion in RbpjiΔEC mice do not originate from hyperplastic or hypertrophic mechanisms; but RbpjiΔEC BECs acquired atypical morphology and increased BEC density along AV shunts, as compared to controls, in postnatal mice. RbpjiΔEC mice also showed reduced regression of BECs over AV connections when studied through empty basement membrane collagen sleeve (EBMS) dynamics, suggesting lack of remodeling and accumulation of BECs over capillary like vessels in vivo. Using isolated postnatal mouse BECs, we found altered small GTPase activity in (open full item for complete abstract)

Committee: Corinne Nielsen (Advisor); Mark Berryman (Committee Member); Fabian Benencia (Committee Chair); Monica Burdick (Committee Co-Chair); Soichi Tanda (Committee Member) Subjects: Biochemistry; Cellular Biology; Genetics; Molecular Biology