Patients with brain arteriovenous malformation (bAVM) are at risk of intracranial hemorrhage (ICH). Overall, bAVM account for 25% of hemorrhagic strokes in adults <50 years of age. The treatment of unruptured lesions has become controversial, because the natural history of these patients may be less morbid than invasive therapies. The mechanism of bAVM formation is not fully understood. There are no specific medical therapies to treat bAVMs. We are among a few groups that have mouse models with bAVM in the brain parenchyma. Using these model, we have identified key factors that are crucial for bAVM formation and progression. We found that the presence of angiogenesis and gene mutation in endothelial cells are essential for bAVM formation. Inflammation may promote bAVM progression. We have also found that bAVM vessels have less mural cell coverage, which is associated with vessel leakage and hemorrhage in mouse bAVMs and in human sporadic bAVMs. Reduction of platelet derived growth factor B (PDGFB) expression in mutant endothelial cells (ECs) might be responsible to the reduction of mural cell coverage. We showed that inhibition of vascular endothelial growth factor (VEGF) signaling through bevacizumab (an anti-VEGF antibody) treatment or intravenous injection of an adeno-associated viral vector (AAV) expressing soluble FMS-related tyrosine kinase 1 (sFLT1) containing the extracellular domain of VEGF receptor 1 inhibits bAVM formation and progression. Increase pericyte coverage by thalidomide treatment reduced the number of abnormal vessels and micro-hemorrhage. The most interesting finding is that homozygous mutation of Alk1 or Eng in a portion of somatic ECs or in bone marrow-derived EC alone is sufficient to trigger de novo bAVM phenotype in the presence of angiogenic stimulation in adult mice. Coincidently, recent studies conducted by others shown that sporadic bAVM and extra-neural AVM harbor somatic mutations in a small number of ECs. It is not clear how a few mutant ECs can cause bAVM formation. In this proposal, we will test our hypothesis that mutant ECs cause bAVM formation and progression through stimulating excessive angiogenesis (Aim 1), impairing pericyte function (Aim 2) and induction of inflammation (Aim 3).
In Aim 1, we will show that mutant ECs undergo clonal expansion and release angiogenic factors to stimulate the proliferation of adjacent normal ECs.
In Aim 2, we will show that mutant EC impair pericyte function through reduction of PDGFB mediated ANG1, TGFb1 and PDGFRb expression in pericytes.
In Aim 3, we will show that mutant EC drives microglia activation, macrophage and lymphocyte infiltration through induction of EC-inflammation. The overarching goal of this project is to identify new therapeutic targets.
Rupture of brain arteriovenous malformation can cause life threatening intra-brain hemorrhage and long- term disability. Currently, it is not clear how the abnormal vessels are formed; and no safe therapy is available to patients. This project will explore the mechanisms underlying the abnormal vessel formation and identify therapeutic targets.
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|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|
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|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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