Brain arteriovenous malformations (AVMs) are characterized by aberrant vascular remodeling, and are an important cause of hemorrhagic stroke in young adults. The etiology and pathogenesis are unknown and better understanding of the molecular events influencing disease susceptibility and clinical progression is needed to optimize patient care. Clinical studies have shown that brain AVMs can occur de novo, and recur after surgical removal, indicating that brain AVMs undergo dynamic remodeling. Data from our group and other investigators have shown that brain AVM nidus had higher levels of angiogenic factors including VEGF, and MMP-9. VEGF and MMP-9 modulate vascular remodeling by promoting vascular cell proliferation/migration, and by recruiting endothelial progenitor cells. Bone marrow-derived endothelial progenitor cells (EPCs) have been shown to play a critical role in postnatal vasculogenesis and vascular homeostasis. EPCs have been well demonstrated to potently initiate and promote tumor neovascularization. In addition, EPCs have been extensively investigated as a risk biomarker and outcome predictor in cardiovascular diseases. Nothing is known about the number and function of EPCs in patients with brain AVMs. Our general hypothesis is that circulating EPCs are recruited to the brain AVM nidus, which, in turn, mediate pathological vascular remodeling and impact the clinical course of brain AVMs.
In aim 1, we will examine whether EPCs are present and increased in the brain AVM nidus using immunohistochemical analysis in 40 archived paraffin-embedded brain AVM tissues. Middle cerebral arteries from 5 autopsies and surgically resected cerebral cortex from 10 epilepsy patients will be used as control. EPCs will be identified using the stem cell marker CD133 and the endothelial cell marker KDR. Stromal cell-derived factor-1 (SDF-1) is a pleiotropic chemokine which has been demonstrated to play a central role in EPC recruitment. We will use immunohistochemical staining to determine whether SDF-1 is expressed in brain AVM nidus. The primary outcome will be EPC levels and correlation of EPC levels with clinical data including demographics, radiographic features of the brain AVMs. The secondary outcome will be SDF-1 expression, and association of SDF-1 expression with EPC number and clinical data.
In aim 2, we will determine whether the number of circulating EPCs is altered in the peripheral blood of brain AVM patients. We will measure circulating EPC number and plasma VEGF level in the prospective cohorts, which include 40 brain AVM patients, and 40 healthy control subjects. The two study cohorts will be age and gender matched. Patients with embolization, radiosurgery, and hemorrhage will be excluded to avoid possible confounding effects. The level of circulating EPCs will be quantified by flow cytometry in blood obtained preoperatively. EPC function will be determined by colony forming units assay. The primary outcome will be EPC number, function and plasma VEGF level. As a secondary analysis, we will measure plasma SDF-1, MMP-9, and nitric oxide levels because these factors have been shown to impact EPC function and migration.

Public Health Relevance

This study represents an important step in developing a novel paradigm to explain the clinical behavior of brain AVMs. Endothelial progenitor cells (EPCs) could be potentially developed as a risk marker for natural history of brain AVM patients. Identification of EPCs as an operant process in brain AVMs can suggest lines of investigation to develop new treatment modalities.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Research Grants (R03)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Jacobs, Tom P
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Gao, Peng; Chen, Yongmei; Lawton, Michael T et al. (2010) Evidence of endothelial progenitor cells in the human brain and spinal cord arteriovenous malformations. Neurosurgery 67:1029-35