Simvastatin Increases Notch Signaling Activity and Promotes Arteriogenesis After Stroke

Abstract

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.

Promoting Neurological Recovery in the Post-Acute Stroke Phase: Benefits and Challenges

“…Acting on VEGF receptor-2 (VEGFR2) that is highly abundant at the tip of new-formed capillaries, VEGF induces endothelial proliferation, and concurrently upregulates the transmembrane ligand Delta-like (Dll)-4, which signals to microvascular cells in the capillary stalk, downregulating VEGFR2 on the stalk cells via interaction with its receptor Notch-1, thus preventing uncontrolled capillary growth [31,32]. This lateral inhibition, which is a key principle underlying structural development during ontogeny, is recapitulated following ischemia [33,34,35]. …”

The effect of simvastatin treatment on proliferation and differentiation of neural stem cells after traumatic brain injury

“…It is also not clear whether simvastatin has similar effect on neurogenic and non-neurogenic region after TBI. The Notch signaling pathway, which plays a key role in multiple cell functions such as differentiation, proliferation, and apoptosis, has been shown to be regulated by simvastatin (Xu et al, 2009;Zacharek et al, 2009). Simvastatin-induced activation of Notch can be inhibited by a gamma-secretase inhibitor, which blocks Notch signaling activity and prevents Notch intracellular domain (NICD) production.…”

Simvastatin ve mevastatin’in anjiogenez inhibisyonu üzerine etkilerinin koryoallantoik membran modelinde araştırılması

“…Zacharek ve ark. [28]; inme geçirmeleri sağlanmış ratlarda, simvastatin"in tedavi dozlarında anjiogenezi artırdığını, damarları stabilize ettiğini ve arteriyogenezi artırdığını göstermişlerdir. Bu çalışmalara zıt şekilde Zhu XY ve ark.…”