Linking Notch signaling to ischemic stroke.
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
Joseph F
JF
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Zhou
Zhipeng
Z
Shin
Hwa Kyoung
HK
Louvi
Angeliki
A
Kim
Hyung-Hwan
HH
Savitz
Sean I
SI
Liao
James K
JK
Salomone
Salvatore
S
Ayata
Cenk
C
Moskowitz
Michael A
MA
Artavanis-Tsakonas
Spyros
S
D000818:Animals; D001011:Aorta / Q000473:pathology / Q000648:ultrastructure; D001158:Arteries / Q000473:pathology / Q000648:ultrastructure; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D002469:Cell Separation; D004198:Disease Susceptibility; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism*; D012039:Regional Blood Flow; D015398:Signal Transduction; D020521:Stroke / Q000150:complications* / Q000378:metabolism* / Q000473:pathology
C499374:NOTCH3 protein, human; C499373:Notch3 protein, mouse; D000071656:Receptor, Notch3; D051880:Receptors, Notch