Brain arteriovenous malformations (AVM) are of unknown etiology and pathogenesis; patients are at life-threatening risk of rupture and intracranial hemorrhage (ICH). This competing continuation will focus on mechanistic animal studies, derived from characterizations of the human AVM tissue, to establish plausible causal chains to explain the human phenotype. The general hypotheses are that non-ischemic venous hypertension (VH) results increases hypoxia inducible factor-1 (HIF-1) expression. Downstream upregulation of vascular endothelial growth factor (VEGF) and inflammatory cytokines, e.g., lnterleukin-6 (IL- 6), initiate the angiogenic phenotype. Consequent increased matrix metalloproteinase (MMP) activity promotes and sustains a nidus of localized angiogenesis. This nidus of excessive angiogenic stimulation, in the presence of abnormal TGF-beta signaling, i.e., endoglin deficiency, leads to creation of malformed microvascular structures.
In Aim 1, using a rat model, we will test the hypotheses that brain HIF-1 is increased by non-ischemic venous hypertension, and decreased by its reversal. We will show that venous hypertension accentuates VEGFinduced angiogenesis, and that HIF-1 blockade abolishes this increase.
In Aim 2, we will test the hypotheses that IL-6 promotes angiogenesis through activation of MMP-9; abrogating IL-6 function will decrease MMP activity. Further, we will demonstrate that leukocyte and macrophage infiltration is associated with local production of MMP expression necessary to promote focal angiogenesis. Techniques include adenoviral gene transfer to overexpress VEGF protein in IL-6 or MMP knock out mice and rescue with GFP-labeled bone marrow-derived cell transplantation (MMP-9) or IL-6 brain infusion.
In Aim 3, we will test the hypotheses that maximizing a pro-angiogenic environment by additional provision of Angiopoietin-2, in conjunction with a novel adeno-associated gene vector transducing VEGF, will further increase the amount of vascular dysplasia. We will then demonstrate that this vascular dysplasia can be attenuated by inhibition of MMP-9 activity using either minocycline or the MMP inhibitor GM6001 These aims will establish potential mechanistic pathways of AVM pathogenesis to guide clinical research and therapy development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS027713-17
Application #
7418294
Study Section
Special Emphasis Panel (ZRG1-BDCN-E (02))
Program Officer
Golanov, Eugene V
Project Start
1990-08-01
Project End
2008-12-31
Budget Start
2008-05-01
Budget End
2008-12-31
Support Year
17
Fiscal Year
2008
Total Cost
$318,370
Indirect Cost
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
Zhu, Wan; Saw, Daniel; Weiss, Miriam et al. (2018) Induction of Brain Arteriovenous Malformation Through CRISPR/Cas9-Mediated Somatic Alk1 Gene Mutations in Adult Mice. Transl Stroke Res :
Wei, Meng; Lyu, Haiyian; Huo, Kang et al. (2018) Impact of Bone Fracture on Ischemic Stroke Recovery. Int J Mol Sci 19:
Zhu, Wan; Chen, Wanqiu; Zou, Dingquan et al. (2018) Thalidomide Reduces Hemorrhage of Brain Arteriovenous Malformations in a Mouse Model. Stroke 49:1232-1240
Zhang, Meng; Deng, Yong-Ning; Zhang, Jing-Yi et al. (2018) SIRT3 Protects Rotenone-induced Injury in SH-SY5Y Cells by Promoting Autophagy through the LKB1-AMPK-mTOR Pathway. Aging Dis 9:273-286
Winkler, Ethan A; Birk, Harjus; Burkhardt, Jan-Karl et al. (2018) Reductions in brain pericytes are associated with arteriovenous malformation vascular instability. J Neurosurg 129:1464-1474
Zhu, Wan; Ma, Li; Zhang, Rui et al. (2017) The roles of endoglin gene in cerebrovascular diseases. Neuroimmunol Neuroinflamm 4:199-210
Zhu, Wan; Shen, Fanxia; Mao, Lei et al. (2017) Soluble FLT1 Gene Therapy Alleviates Brain Arteriovenous Malformation Severity. Stroke 48:1420-1423
Zou, Dingquan; Luo, Man; Han, Zhenying et al. (2017) Activation of Alpha-7 Nicotinic Acetylcholine Receptor Reduces Brain Edema in Mice with Ischemic Stroke and Bone Fracture. Mol Neurobiol 54:8278-8286
Su, Hua (2017) Inflammation and genetic factors in stroke pathogenesis. Neuroimmunol Neuroinflamm 4:260-262
Ma, Li; Kim, Helen; Chen, Xiao-Lin et al. (2017) Morbidity after Hemorrhage in Children with Untreated Brain Arteriovenous Malformation. Cerebrovasc Dis 43:231-241

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