Department of Molecular and Experimental Medicine
Faculty, Graduate Program
Regulation of Cerebral Angiogenesis by the Extracellular Matrix
The goal of our research is to understand how extracellular matrix (ECM) proteins regulate blood vessel growth in the central nervous system (CNS). During development, endothelial cells switch from an angiogenic phenotype into a stable differentiated phenotype, and this coincides with a switch in expression, from fibronectin receptors during angiogenesis, to laminin receptors in the adult. In vitro studies reveal that fibronectin strongly promotes brain endothelial cell survival and proliferation, and that this effect is mediated via the fibronectin receptors, α5β1 and αvβ3 integrins. To examine whether angiogenesis in the adult CNS is also associated with induction of fibronectin and its receptors we examined this process in a mouse model of hypoxia. In the hypoxic CNS, fibronectin and the α5β1 integrin were strongly upregulated on angiogenic vessels, suggesting that the α5β1 integrin may be important in driving angiogenesis in the adult CNS. Currently we are using knockout mice and a combination of in vivo and in vitro approaches to define the roles of the α5β1 and αvβ3 integrins at specific stages of cerebral angiogenesis.
Ph.D., Developmental Neurobiology, University of Cambridge, 1994
M.D., Medicine and Surgery, University of Cambridge, 1998
B.S., Physiology, University of Leeds, 1990
2004 - Wellcome Trust Career Development Fellowship (University of Cambridge)
2006 - Harry Weaver Neuroscience Scholar Award from The National Multiple Sclerosis Society (one of only two awarded nationwide in 2006)
Milner, R., Crocker S.J., Hung, S., Wang, X., Frausto, R.F. & del Zoppo G.J. (2007) Fibronectin and vitronectin induced microglial activation and matrix metalloproteinase-9 expression is mediated by integrins α5β1 and α5β1. J. Immunol. 178, 8158-8167.
Milner, R., Hung, S., Wang, X., Berg, G. & del Zoppo, G.J. (2008). Responses of endothelial cell and astrocyte matrix-integrin receptors to ischemia mimic those observed in the neurovascular unit. Stroke. 39, 191-7.
Milner, R., Hung, S., Wang, X., Spatz, M. & del Zoppo, G.J. (2008). The rapid decrease in astrocyte-associated dystroglycan expression by focal cerebral ischemia is protease-dependent. J. Cereb. Blood Flow Metab. 28, 812-23.
Milner, R., Hung, S., Erokwu, B., Dore-Duffy, P., LaManna, J.C., & del Zoppo, G.J. (2008). Increased expression of fibronectin and the α5β1 integrin in angiogenic cerebral blood vessels of mice subject to hypobaric hypoxia. Mol. Cell. Neurosci. 38, 43-52.