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.

Arboleda-Velasquez JF, Zhou Z, Shin HK, Louvi A, Kim HH, Savitz SI, Liao JK, Salomone S, Ayata C, Moskowitz MA, Artavanis-Tsakonas S.

Department of Cell Biology, Harvard Medical School, Boston, MA 02115;