Brain arteriovenous malformation (AVM) patients are at risk of rupture and intracranial hemorrhage (ICH). The etiopathogenesis is unknown and research progress is critically hampered by the lack of animal models. There is no medical therapy available to directly treat AVMs or decrease the spontaneous rupture risk. The only options are resection, embolization and radiotherapy, all of which may pose significant risk. To study potential mechanisms for AVM pathogenesis, surrogate models of the lesion phenotype are needed. To that end, we have developed a quantifiable surrogate phenotype that may represent early stages of AVM formation, which we term vascular dysplasia (dilated, dysmorphic vessels). We use viral-mediated focal brain VEGF stimulation of mice with either endoglin (ENG) or activin-like kinase 1 (ALK1) haploinsufficiency. These animals display dysmorphic and enlarged microvascular structure. The approach is grounded on human observations of increased VEGF expression in lesional tissue and the similarity of sporadic AVM to those seen in patients with ENG or ALK1 mutations.
Aim 1 : Altered hemodynamics contributes to the dysplastic response. Venous hypertension and high intravascular flow rates are a prominent part of the vascular environment in clinical disease but how such changes contribute to lesion formation or progression is poorly understood. We will test the effect of increased flow and venous pressure, and their interaction to produce dysplasia. In the VEGF- stimulated brain, we hypothesize that mice heterozygous for either ENG or ALK1 mice will show an increased dysplastic response to increased flow and/or increased venous pressure.
Aim 2 : Vascular dysplasia from ENG deficiency is contingent on bone marrow derived cells (BMDC). Based on preliminary data, we hypothesize that it is the ENG haploinsufficient BMDC driving the dysplastic response after VEGF stimulation. Sub-aims will use ICAM-1 deficient (-/-) mice as recipients to interfere with ENG BMDC recruitment to the angiogenic focus, to demonstrate that reduction of BMDC recruitment mitigates the dysplastic response;and to investigate whether the hematopoietic stem cells in ENG bone marrow are the primary component of the response.
Aim 3 : Focal abrogation of downstream signaling using extracellular domains of ENG and ALK1 results in vascular dysplasia. Resected AVM tissue displays an increased amount of soluble ENG (sENG), compared to control brain. We hypothesize that focal overexpression of sENG or soluble ALK1 (sALK1), in tandem with VEGF, will mimic the brain phenotype observed in ENG and ALK1 mice after focal brain VEGF stimulation. These studies will provide better understanding of the determinants of the surrogate vascular phenotype. The work will allow development of an animal model to test mechanistic hypotheses that are pertinent to development of novel therapeutics that can beneficially alter the natural history of AVMs.

Public Health Relevance

Brain arteriovenous malformation (AVM) patients are at risk of rupture and intracranial hemorrhage (ICH). The etiopathogenesis is unknown and research progress is critically hampered by the lack of animal models. There is no medical therapy available to directly treat AVMs or decrease the spontaneous rupture risk. These studies will provide better understanding of the determinants of a novel surrogate vascular phenotype that models aspects of the disease. The work will allow development of an animal model to test mechanistic hypotheses that are pertinent to development of novel therapeutics that can beneficially alter the natural history of AVMs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS027713-22
Application #
8415938
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Koenig, James I
Project Start
1990-08-01
Project End
2013-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
22
Fiscal Year
2013
Total Cost
$319,617
Indirect Cost
$112,745
Name
University of California San Francisco
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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