Neurological Injury and Disease
Department of Neurosurgery, UCSF
Principal Investigators
Shirley I. Stiver M.D., Ph.D.
Laboratory Members
Dong Mei Shao
Laboratory Mission Statement
The goal of our laboratory is to understand and modulate properties of cerebral vessels for the treatment of neurological injury and disease processes.
General Overview
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Angiogenic vasculature
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Our laboratory investigates the role of the vasculature in neurological processes. Specifically we are interested in understanding new blood vessel growth in brain (cerebral angiogenesis) that accompanies many types of neurological injury, including brain tumor formation, head trauma, and stroke. Our current research focuses on the structure and function of new angiogenic vessels induced by vascular endothelial growth factor (VEGF-A). VEGF-A is one of the most potent stimuli for new blood vessel growth and expression is strongly up-regulated in brain during neurological injury and disease. The ultimate goal of these studies is to develop new strategies targeted to angiogenic vessels for treatment of patients with these neurological problems.
Areas of Focus
Mechanisms of VEGF-A Cerebral Angiogenesis
A) One micron sections of striatum treated with adenoviral VEGF-A demonstrate clusters of angiogenic vessels and increased vessel density at 12 months (arrows).
Augmentation of the cerebral vasculature following adenoviral VEGF-A treatment is evident when compared to B) the vasculature (arrow) in normal striatum. .
We have extensive experience with the use of adenoviruses, in a murine model of cerebral angiogenesis, to elaborate levels of VEGF-A that recapitulate those in neurological disease. Our previous research established that VEGF-A induced the formation of angiogenic vessels that augmented the pre-existing vasculature. The finding that this neovasculature was stable indefinitely, even after subsidence of exogenous VEGF-A expression, achieved a long-sought goal of angiogenesis research. Investigation of the structure and function of angiogenic vessels is a major focus of study, as understanding how the properties of angiogenic vessels differ from the normal cerebral vasculature is requisite to applications of angiogenesis for therapeutic benefit.
Blood-Brain Barrier Properties of Angiogenic Vessels
FITC-labeled 70MW-dextrans, circulated intravenously, extravasate across angiogenic vessels into the brain parenchyma.
The first objective of our current studies is to understand how the function of angiogenic vessels differs from that of normal brain blood vessels. In particular, we are interested in the blood-brain-barrier and permeability characteristics of angiogenic vessels. For these experiments, animals are inoculated in the brain with virus expressing VEGF-A. At serial time points, tracers and drugs of different size and character are injected into the blood stream and transport across the angiogenic endothelium is measured by various techniques. These studies are important for understanding brain edema that accompanies malignant brain tumor formation, stroke, and head injury.
Therapeutic Angiogenesis in Animal Models of Neurological Disease
Angiogenesis is an important component of the pathophysiology of stroke and traumatic head injury. A major objective of our laboratory is to study therapeutic applications of angiogenesis in animal models of neurological disease.
Stroke.
Mice treated with adenoviral VEGF-A and control adenoviral LacZ are subjected to middle cerebral ischemia. Sections stained with 2% 2,3,5-triphenyltetrazolium chloride (TTC) show reduced infarct volumes in treated mice.
We have developed animal models of ischemia and are studying whether VEGF-A can ameliorate stroke through either augmented angiogenesis or by acting as a neuronal survival factor. Animals treated with adenoviral VEGF-A are subjected to an ischemic insult and infarct volumes and neuronal survival rates are measured and compared to control animals.
Traumatic Brain Injury.
Human and experimental data evidence that VEGF-A is up-regulated and contributes to the development of angiogenesis as well as brain edema following traumatic brain injury. We are using experimental animal models as well as clinical studies in the intensive care unit to investigate how VEGF-A angiogenesis and blood-brain barrier permeability may impact patient outcome following head injury.
Hematoxylin & eosin-stained sections from mice subjected to a controlled cortical head injury show angiogenesis around the injury site.
Funding
SI Stiver, NIH K08 NS 02236 : Mechanisms of VPF/VEGF-induced cerebral angiogenesis
Selected Publications
Stiver SI, Porter PJ, Willinsky, Wallace MC. Acute human histopathology of an intracranial aneurysm treated with Guglielmi Detachable Coils: Case report and review of the literature, Neurosurgery 43: 1203-1208, 1998.
Stiver SI, Ogilvy CS. Micro-AVMs: Significant hemorrhage from small arterio-venous shunts, Neurosurgery 46: 811-819, 2000.
Stiver SI, Dvorak HF. Vascular Permeability Factor/Vascular Endothelial Growth Factor (VPF/VEGF), J Clin Ligand Assay 23: 193-205, 2000.
Stiver SI, Tan X, Brown LF, Hedley-Whyte ET, Dvorak, HF. VEGF-A induces a stable neovasculature in adult murine brain, J Neuropathol Exp Neurol 63(8):841-55, 2004.
Stiver SI. Angiogenesis and its role in the behavior of astrocytic brain tumors, Front Biosci 9: 3105-23 (2004).
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