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Full text release has been delayed at the author's request until September 01, 2026

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Impairment in Postnatal Cerebrovascular Remodeling Mediated by Small GTPases in Endothelial Rbpj Deficient Brain Arteriovenous Malformation

Adhicary, Subhodip
http://orcid.org/0000-0003-2299-8871
http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1651761209984319

Abstract Details

2022, Doctor of Philosophy (PhD), Ohio University, 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 RbpjiΔEC vs. control. Additionally, siRNA mediated silencing of RBPJ in human brain microvascular cells, corroborated altered GTPase activity, and led to reduced migration, disrupted cell polarity, and altered focal adhesion properties, in vitro. These data suggest that Rbpj regulates small GTPase-mediated focal adhesion assembly, and RBPJ is required for directed movement of BECs. Administration of a competitive peptide antagonist against the Apelin receptor (APLR/APJ), or neutralizing antibody against Osteopontin (SPP1/OPN) – molecules that were found to be upregulated through mRNA sequencing at P7, ameliorated BEC morphology and reduced AV diameter in P14 RbpjiΔEC mice. Moreover, isolated BECs from treated RbpjiΔEC mice showed restoration of GTPase activity. Overall, our findings indicate that endothelial Rbpj is essential in maintaining healthy BEC morphology and movement/rearrangement, by regulating cell polarity and small GTPase-mediated focal adhesion properties, promoting cerebrovascular alignment and remodeling along normal AV connections, thereby preventing BAVM, and offer proof of concept for therapeutic potential of Apelin and Osteopontin in BAVM pathophysiology.
Corinne Nielsen (Advisor)
Mark Berryman (Committee Member)
Fabian Benencia (Committee Chair)
Monica Burdick (Committee Co-Chair)
Soichi Tanda (Committee Member)
Biochemistry; Cellular Biology; Genetics; Molecular Biology
brain arteriovenous malformation; brain endothelial cells; Notch signaling; Rbpj; postnatal vascular remodeling

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Citations

  • Adhicary, S. (2022). Impairment in Postnatal Cerebrovascular Remodeling Mediated by Small GTPases in Endothelial Rbpj Deficient Brain Arteriovenous Malformation [Doctoral dissertation, Ohio University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1651761209984319

    APA Style (7th edition)

  • Adhicary, Subhodip. Impairment in Postnatal Cerebrovascular Remodeling Mediated by Small GTPases in Endothelial Rbpj Deficient Brain Arteriovenous Malformation. 2022. Ohio University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1651761209984319.

    MLA Style (8th edition)

  • Adhicary, Subhodip. "Impairment in Postnatal Cerebrovascular Remodeling Mediated by Small GTPases in Endothelial Rbpj Deficient Brain Arteriovenous Malformation." Doctoral dissertation, Ohio University, 2022. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1651761209984319

    Chicago Manual of Style (17th edition)

ohiou1651761209984319
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This open access ETD is published by Ohio University and OhioLINK.