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Ulrich Laufs, Matthias Endres, Nancy Stagliano, Sepideh Amin-Hanjani, Dao-Shan Chui, Shui-Xiang Yang, Tommaso Simoncini, Masaru Yamada, Elena Rabkin, Philip G. Allen, Paul L. Huang, Michael Böhm, Frederick J. Schoen, Michael A. Moskowitz, James K. Liao
J Clin Invest. 2000;
106(1):15
doi:10.1172/JCI9639
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erebral blood flow is regulated by endothelium-derived nitric oxide (NO), and endothelial NO synthase–deficient (eNOS-deficient; eNOS–/–) mice develop larger cerebral infarctions following middle cerebral artery (MCA) occlusion. We report that disruption of Rho-mediated endothelial actin cytoskeleton leads to the upregulation of eNOS expression and reduces the severity of cerebral ischemia following MCA occlusion. Mice treated with the Rho inhibitor Clostridium botulinum C3 transferase (10 μg/d) or the actin cytoskeleton disrupter cytochalasin D (1 mg/kg) showed a two- to fourfold increase in vascular eNOS expression and activity. This increase in eNOS expression was not due to increases in eNOS gene transcription, but to prolongation of eNOS mRNA half-life from 10 ± 3 hours to 24 ± 4 hours. Indeed, endothelial cells overexpressing a dominant-negative Rho mutant (N19RhoA) exhibited decreased actin stress fiber formation and increased eNOS expression. Inhibition of vascular Rho guanosine-5′-triphosphate binding activity by the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor simvastatin increased cerebral blood flow to ischemic regions of the brain, and mice treated with simvastatin, C3 transferase, or cytochalasin D showed smaller cerebral infarctions following MCA occlusion. No neuroprotection was observed with these agents in eNOS–/– mice. These findings suggest that therapies which target the endothelial actin cytoskeleton may have beneficial effects in ischemic stroke.
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