The phosphorylation state of eNOS modulates vascular reactivity and outcome of cerebral ischemia in vivo
Dmitriy N. Atochin, Annie Wang, Victor W.T. Liu, Jeffrey D. Critchlow, Ana Paula V. Dantas, Robin Looft-Wilson, Takahisa Murata, Salvatore Salomone, Hwa Kyoung Shin, Cenk Ayata, Michael A. Moskowitz, Thomas Michel, William C. Sessa, Paul L. Huang
Dmitriy N. Atochin, Annie Wang, Victor W.T. Liu, Jeffrey D. Critchlow, Ana Paula V. Dantas, Robin Looft-Wilson, Takahisa Murata, Salvatore Salomone, Hwa Kyoung Shin, Cenk Ayata, Michael A. Moskowitz, Thomas Michel, William C. Sessa, Paul L. Huang
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Research Article Hematology

The phosphorylation state of eNOS modulates vascular reactivity and outcome of cerebral ischemia in vivo

Abstract

NO plays critical roles in vascular function. We show that modulation of the eNOS serine 1179 (S1179) phosphorylation site affects vascular reactivity and determines stroke size in vivo. Transgenic mice expressing only a phosphomimetic (S1179D) form of eNOS show greater vascular reactivity, develop less severe strokes, and have improved cerebral blood flow in a middle cerebral artery occlusion model than mice expressing an unphosphorylatable (S1179A) form. These results provide a molecular mechanism by which multiple diverse cardiovascular risks, such as diabetes and obesity, may be centrally integrated by eNOS phosphorylation in vivo to influence blood flow and cardiovascular disease. They also demonstrate the in vivo relevance of posttranslational modification of eNOS in vascular function.

Authors

Dmitriy N. Atochin, Annie Wang, Victor W.T. Liu, Jeffrey D. Critchlow, Ana Paula V. Dantas, Robin Looft-Wilson, Takahisa Murata, Salvatore Salomone, Hwa Kyoung Shin, Cenk Ayata, Michael A. Moskowitz, Thomas Michel, William C. Sessa, Paul L. Huang

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Figure 5

Effect of S1179A and S1179D eNOS mutations on cerebral infarct size.

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Effect of S1179A and S1179D eNOS mutations on cerebral infarct size. Mic...
Mice were subjected to the filament model of MCA occlusion for 1 hour, followed by 23 hours of reperfusion. The brains were cut into 2-mm coronal sections and stained using 2,3,5-triphenyltetrazolium chloride. (A) Rostral to caudal distribution of infarct areas (mm2) in coronal sections. Abscissa shows the distance (mm) from the rostral surface of the brain. n = 7 mice for each group. *P < 0.05 versus corresponding sections from S1179A/eNOS KO mice; †P < 0.05 versus corresponding sections from eNOS KO mice using 1-way ANOVA. (B) Infarct volumes were determined by integrating the infarct areas in each section over the entire brain, using the indirect method, which corrects for edema. *P < 0.05 versus infarct volume from S1179A/eNOS and from eNOS KO mice using ANOVA. Neurologic scores for each group of mice are as follows: eNOS KO, 2.5; S1179A/eNOS KO, 2.67; S1179D/eNOS KO, 1.57; WT, 1.86. Kruskal-Wallis 1-way ANOVA on ranks showed a statistically significant difference between eNOS KO and S1179A/eNOS KO mice and WT and S1179D/eNOS KO mice (P < 0.05).