Brain arteriovenous malformations (BAVMs) can cause stroke and epilepsy and have no effective treatment. BAVMs are abnormal arteriovenous (AV) shunts that are not believed to regress spontaneously, but rather are prone to dangerous rupture. The cellular and molecular basis of BAVM pathogenesis remains enigmatic. Our long-term objectives are to elucidate the mechanisms of BAVM pathogenesis and to identify novel therapeutic targets to ameliorate this disease. Our general strategy is to take a cross-disciplinary approach fusing cutting-edge mouse genetics and imaging technologies to determine the function of critical molecular pathways that normally regulate AV differentiation, such as Notch signaling, in the pathogenesis of BAVM. We have reported a faithful transgenic mouse model of BAVMs, in which expression of constitutively-active Notch4 (Notch4*) specifically in endothelium elicits hallmarks of BAVMs in immature mice. Furthermore, the areas within the developing brain which grow most rapidly, likely the most angiogenic, were most susceptible to Notch4* effects, suggesting that angiogenesis underlies BAVM formation. Repression of Notch4* expression in severely affected mice resulted in a reversal of neurologic symptoms and recovery from the illness, suggesting that BAVM-like lesions can regress in animals when the molecular cause is removed. We have also reported that Notch activity is increased in the endothelium of human BAVMs, suggesting that Notch signaling may act as a molecular mediator in the human disease. Here we hypothesize that Notch4* during angiogenesis inhibits a capillary number increase, thus promoting the enlargement of capillary diameter, which initiates and sustains AV shunts that catalyze BAVM formation.
Our specific aims are designed to elucidate the mechanisms of Notch4*-mediated onset, progression, and regression of BAVM-like lesions in mice. We will combine our mouse model of BAVM with advanced 2-photon imaging to obtain 4D vascular morphology at cellular resolution and blood velocity data in living brains. Our custom-built 2-photon microscope, optimal for cerebral vascular imaging, makes this innovative study possible.
Aim1 Examine the angiogenic mechanism by which Notch4* elicits BAVM-like lesions in mice.
Aim2 Examine lateral induction as a potential mechanism by which Notch4* propagates Notch signaling in cerebral endothelium.
Aim3 Determine the cellular mechanism underlying the regression of AV shunting upon Notch4* repression. Successful completion of this study will conceptually advance our understanding of the cellular and molecular mechanisms of BAVM pathogenesis and help establish new paradigms in the knowledge and treatment of BAVMs. Our establishment of 2-photon high resolution imaging to study BAVM development in living animals will be a major technological innovation for BAVM research at large.

Public Health Relevance

Brain arteriovenous malformations (BAVMs) are abnormal connections between arteries and veins that can cause stroke and epilepsy. There is currently no effective treatment for BAVMs, which are conventionally believed to not regress, although recent evidence suggests regression is possible. This proposal is designed to determine the molecular pathways underlying BAVM formation and regression, with the hope of identifying novel therapeutic targets to treat this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS067420-03
Application #
8269939
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Koenig, James I
Project Start
2010-08-01
Project End
2013-09-29
Budget Start
2012-06-01
Budget End
2013-09-29
Support Year
3
Fiscal Year
2012
Total Cost
$293,778
Indirect Cost
$94,289
Name
University of California San Francisco
Department
Surgery
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Hwa, Jennifer J; Beckouche, Nathan; Huang, Lawrence et al. (2017) Abnormal arterial-venous fusions and fate specification in mouse embryos lacking blood flow. Sci Rep 7:11965
Nielsen, Corinne M; Huang, Lawrence; Murphy, Patrick A et al. (2016) Mouse Models of Cerebral Arteriovenous Malformation. Stroke 47:293-300
Cuervo, Henar; Nielsen, Corinne M; Simonetto, Douglas A et al. (2016) Endothelial notch signaling is essential to prevent hepatic vascular malformations in mice. Hepatology 64:1302-1316
Murphy, Patrick A; Kim, Tyson N; Huang, Lawrence et al. (2014) Constitutively active Notch4 receptor elicits brain arteriovenous malformations through enlargement of capillary-like vessels. Proc Natl Acad Sci U S A 111:18007-12
Lin, Yuankai; Jiang, Weiya; Ng, Jennifer et al. (2014) Endothelial ephrin-B2 is essential for arterial vasodilation in mice. Microcirculation 21:578-86
Nielsen, Corinne M; Cuervo, Henar; Ding, Vivianne W et al. (2014) Deletion of Rbpj from postnatal endothelium leads to abnormal arteriovenous shunting in mice. Development 141:3782-92
Kim, Tyson N; Goodwill, Patrick W; Chen, Yeni et al. (2012) Line-scanning particle image velocimetry: an optical approach for quantifying a wide range of blood flow speeds in live animals. PLoS One 7:e38590
Murphy, Patrick A; Kim, Tyson N; Lu, Gloria et al. (2012) Notch4 normalization reduces blood vessel size in arteriovenous malformations. Sci Transl Med 4:117ra8