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(Stroke. 2009;40:254.)
© 2009 American Heart Association, Inc.

Original Contributions

Simvastatin Increases Notch Signaling Activity and Promotes Arteriogenesis After Stroke

Alex Zacharek, MS; Jieli Chen, MD; Xu Cui, PhD; Yuping Yang, MD Michael Chopp, PhD

From Department of Neurology (A.Z., J.C., X.C., Y.Y., M.C.), Henry Ford Hospital, Detroit, Mich; Department of Physics (M.C.), Oakland University, Rochester, Mich.

Correspondence to Jieli Chen, MD, Neurology Research, E&R Building, Room #3091, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202. E-mail jieli{at}neuro.hfh.edu

Background and Purpose— Notch signaling activity regulates arteriogenesis. Presenilin 1 (PS1) mediates Notch signaling activity via cleavage of Notch, liberating Notch intracellular domain (NICD). We tested the hypothesis that simvastatin enhances arteriogenesis after stroke by increasing PS1 activation of the Notch signaling pathway.

Methods— Rats were subjected to middle cerebral artery occlusion (MCAo) and treated with or without simvastatin (1 mg/kg) starting 24 hours after stroke and daily for 7 days; they were euthanized 14 days after stroke. Immunostaining, Western blot, and real-time polymerase chain reaction assays were performed.

Results— Simvastatin significantly increased arterial diameter, density, and vascular smooth muscle cell proliferation, and upregulated PS1, Notch1, and NICD expression in the ischemic border tissue and in the cerebral arteries compared with MCAo control rats, respectively. However, simvastatin did not increase arteriogenesis, PS1, and NICD expression in sham control animals. To investigate the mechanisms of simvastatin-induced arteriogenesis, primary cerebral artery cultures were used. Rats were subjected to MCAo and treated with or without simvastatin daily for 7 days. The cerebral arteries derived from these stroke rats were cultured in matrigel and treated with or without a 40-secretase inhibitor II, which blocks Notch signaling activity, inhibiting NICD production. Arterial cell migration was measured. simvastatin treatment significantly increased arterial cell migration compared to control MCAo artery, whereas inhibition of Notch signaling activity by the 40-secretase inhibitor II significantly attenuated simvastatin-induced arterial cell migration.

Conclusions— These data indicate that simvastatin increases arteriogenesis after stroke, and that simvastatin upregulation of PS1 expression and Notch signaling activity may facilitate an increase in arteriogenesis.

Key Words: arteriogenesis • Notch signaling • presenilin 1 • simvastatin • stroke