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Molecular and Cellular Biology, November 2002, p. 7667-7677, Vol. 22, No. 21
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.21.7667-7677.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Defective Associations between Blood Vessels and Brain Parenchyma Lead to Cerebral Hemorrhage in Mice Lacking {alpha}v Integrins

Joseph H. McCarty,1 Rita A. Monahan-Earley,2 Lawrence F. Brown,2 Markus Keller,3 Holger Gerhardt,4 Kristofer Rubin,5 Moshe Shani,6 Harold F. Dvorak,2 Hartwig Wolburg,4 Bernhard L. Bader,3 Ann M. Dvorak,2 and Richard O. Hynes1*

Howard Hughes Medical Institute and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139,1 Department of Pathology, Beth Israel-Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts 02215,2 Department of Protein Chemistry, Max Planck Institute for Biochemistry, Martinsried, Munich, Germany,3 Institute of Pathology, University of Tübingen, Tübingen, Germany,4 Department of Medical and Physiological Chemistry, University of Uppsala, Uppsala, Sweden,5 Institute for Animal Science, The Volcani Institute, Bet Dagan, Israel6

Received 17 June 2002/ Accepted 1 August 2002

Mouse embryos genetically null for the {alpha}v integrin subunit develop intracerebral hemorrhages at midgestation and die shortly after birth. A key question is whether the hemorrhage arises from primary defects in vascular endothelial cells or pericytes or from other causes. We have previously reported normal initiation of cerebral vessels comprising branched tubes of endothelial cells. Here we show that the onset of hemorrhage is not due to defects in pericyte recruitment. Additionally, most {alpha}v-null vessels display ultrastructurally normal endothelium-pericyte associations and normal interendothelial cell junctions. Thus, endothelial cells and pericytes appear to establish their normal relationships in cerebral microvessels. However, by both light and electron microscopy, we detected defective associations between cerebral microvessels and the surrounding brain parenchyma, composed of neuroepithelial cells, glia, and neuronal precursors. These data suggest a novel role for {alpha}v integrins in the association between cerebral microvessels and central nervous system parenchymal cells.

* Corresponding author. Mailing address: M.I.T. E17-230, Cambridge, MA 02139. Phone: (617) 253-6422. Fax: (617) 253-8357. E-mail: rohynes{at}mit.edu.

Molecular and Cellular Biology, November 2002, p. 7667-7677, Vol. 22, No. 21
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.21.7667-7677.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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