Linking Notch signaling to ischemic stroke

*Department of Cell Biology, Harvard Medical School, Boston, MA 02115;
^†Stroke and Neurovascular Regulation Laboratory, Massachusetts General Hospital, Boston, MA 02129;
^‡Program on Neurogenetics and Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520;
^§Vascular Medicine Research Unit, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139; and
^¶Collège de France, 75231 Paris, France

Edited by Pietro V. De Camilli, Yale University School of Medicine, New Haven, CT, and approved January 15, 2008 (received for review October 16, 2007)

Abstract

Vascular smooth muscle cells (SMCs) have been implicated in the pathophysiology of stroke, the third most common cause of death and the leading cause of long-term neurological disability in the world. However, there is little insight into the underlying cellular pathways that link SMC function to brain ischemia susceptibility. Using a hitherto uncharacterized knockout mouse model of Notch 3, a Notch signaling receptor paralogue highly expressed in vascular SMCs, we uncover a striking susceptibility to ischemic stroke upon challenge. Cellular and molecular analyses of vascular SMCs derived from these animals associate Notch 3 activity to the expression of specific gene targets, whereas genetic rescue experiments unambiguously link Notch 3 function in vessels to the ischemic phenotype.

Footnotes

^‖To whom correspondence should be addressed. E-mail: artavanis{at}hms.harvard.edu
Author contributions: J.F.A.-V. and Z.Z. contributed equally to this work; J.F.A.-V., Z.Z., A.L., S.S., C.A., M.A.M., and S.A.-T. designed research; J.F.A.-V., Z.Z., H.K.S., A.L., H.-H.K., S.I.S., S.S., and C.A. performed research; J.F.A.-V., Z.Z., H.K.S., A.L., H.-H.K., S.I.S., J.K.L., S.S., C.A., M.A.M., and S.A.-T. analyzed data; and J.F.A.-V., A.L., C.A., M.A.M., and S.A.-T. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0709867105/DC1.