Sunday, May 5, 2024
5/5/2024
Project Summary/Abstract Mechanisms regulating vascular homeostasis are necessary for proper tissue development and lifelong organismal health. Despite its critical importance to the central nervous system, mechanisms governing the vascular supply to the brain are largely unknown. Brain arteriovenous malformation (AVM) is a clinically defined neurovascular disease that alters blood vessel form and function and ultimately affects neurological health. Though a relatively rare disorder, brain AVM puts patients at risk for hemorrhagic stroke, ischemia, and neurological deficit, making its study broadly relevant to the neurovascular field. In this application, we propose in vivo and in vitro approaches to examine perivascular cells (pericytes) during the pathogenesis of Notch induced brain AVM. We use a genetic mouse model of brain AVM, in which we use CreERT2 to delete Rbpj (a transcription factor downstream of canonical Notch) in a spatially and temporally restricted manner – deletion from endothelial cells (ECs), induced at birth. This genetic manipulation leads to clinically defined features of brain AVM, including direct arteriovenous shunting, increased endothelial area per brain tissue area, and 50% lethality within two weeks (by postnatal day (P) 14). Preliminary evidence described in this proposal indicate that: 1) pericyte coverage of vascular endothelium keeps pace with increasing endothelial area during Rbpj mediated brain AVM pathogenesis, 2) pericyte coverage is regionally regulated in the brain, 3) endothelial Rbpj deficiency alters PDGF/PDGFRß signaling in pericytes. We propose to study consequences to pericyte cells, in the context of this genetic deletion and disease pathogenesis, and to test our central hypothesis that pericyte expansion and PDGF/PDGFRß-dependent EC:pericyte associations are affected, directly or indirectly, during the pathogenesis of Rbpj mediated brain AVM. This hypothesis will be addressed in two specific aims. In the first aim, pericyte number and coverage of postnatal brain endothelium will be examined in Rbpj-brain AVM. In the second aim, PDGF-dependent association between ECs and pericytes will be determined during Rbpj-brain AVM pathogenesis. These studies will advance our long term research objectives, which are: 1) to further our understanding of the cellular and molecular mechanisms of brain AVM initiation, progression, and maintenance; 2) to determine whether pericytes are actively involved in brain AVM pathogenesis; 3) to determine if the pericyte cell population may be an effective therapeutic target in the treatment of brain AVM. Collaborating with student researchers toward these research goals will support the mission to provide a meritorious research experience to emerging scientists and clinician-scientists.
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