Abstract TP257: Endothelial Cell and Smooth Muscle Cell Specific Tsc1 Deficiency are Important Mediators of Ischemic Stroke
Background and Purpose: To determine the function of Tsc1 in endothelial cells (Tie2CreTsc1flox/+) and vascular smooth muscle cells (SM22CreTsc1flox/flox) in transient focal cerebral ischemia, we hypothesized that Tsc1 deficiency in endothelial cells and smooth muscle cells may play an important role in ischemic stroke via mTOR/S6 signaling pathways.
Methods: To determine the effect of endothelial cell and smooth muscle cell specific Tsc1 deficiency in transient focal cerebral ischemia, we generated Tie2CreTsc1flox/+ and SM22CreTsc1flox/flox mice. Crossing floxed Tsc1 with Tie2Cre and SM22Cre transgene mice expressing Cre recombinase in endothelial cells (ECs) and smooth muscle cells (SMCs) resulted in mice in which vascular SMC mRNA expression was reduced by approximately 70~80%. Isoflurane-anesthetized Tie2Cre, SM22Cre, Tie2CreTsc1flox/+, SM22CreTsc1flox/+ and SM22CreTsc1flox/flox mice (20-22g) underwent 2h focal cerebral ischemia (Middle Cerebral Artery Occlusion; MCAO) induced with a 8.0 nylon monofilament coated with a silicone resin/hardener mixture introduced into the left internal carotid artery up to the anterior cerebral artery.
Results: Compared to control (Tie2Cre and SM22Cre) mice, Tie2CreTsc1flox/+, SM22CreTsc1flox/+, and SM22CreTsc1flox/flox mice decreased cerebral infarct size (45.5 ± 11.8 mm3 (p<0.001), 51.0 ± 6.1 mm3 (p<0.001) and 31.8 ± 11.9 mm3 (p<0.001) vs. 92.6 ± 6.1 mm3, n=5-10) and improved neurological deficit score (2.0 ± 0.5, 2.4 ± 0.3 and 1.6 ± 0.2 (p<0.01) vs. 3.0 ± 0.2, n=5-10) versus control mice. Infarction volume was reduced via activation of mTOR and S6, a downstream target of mTORC1 in both endothelial cell and smooth muscle cell specific Tsc1 deficient mice.
Conclusion: These results suggest that endothelial cell and smooth cell specific Tsc1 deficiency are important mediators of ischemic stroke via mTOR signaling pathways.
- © 2012 by American Heart Association, Inc.