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Stroke. 2013 Nov;44(11):3183-8. doi: 10.1161/STROKEAHA.113.002073. Epub 2013 Aug 29.

Deficient eNOS phosphorylation is a mechanism for diabetic vascular dysfunction contributing to increased stroke size.

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From the Cardiovascular Research Center (Q.L., D.A., S.K., J.E., A.W., P.L.H.) and Neuroprotection Research Laboratory (E.M., K.H., E.H.L.), Massachusetts General Hospital and Harvard Medical School, Boston, MA; the Departments of Anesthesiology and Molecular, Pharmacology, and Experimental Therapeutics, Mayo Clinic, Rochester, MN (L.V.U., Z.K.); and the Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT (W.S.).



Phosphorylation of eNOS, an important post-translational modulator of its enzymatic activity, is reduced in diabetes mellitus. We hypothesized that modulation of eNOS phosphorylation could overcome diabetic vascular dysfunction and improves the outcome to stroke.


We used the db/db mouse model of type 2 diabetes mellitus. We mated db/db mice with eNOS knock-in mice that carry single amino acid mutations at the S1176 phosphorylation site; the phosphomimetic SD mutation (serine replaced by aspartate) shows increased eNOS enzymatic activity, whereas the unphosphorylatable SA mutation (serine replaced by alanine) shows decreased eNOS activity. We characterized the vascular anatomy, baseline physiological parameters, and vascular reactivity. We used the middle cerebral artery occlusion model of stroke and measured infarct volume and neurological deficits.


db/db mice showed diminished eNOS phosphorylation at S1176. eNOS SD and SA mutations do not change the vascular anatomy at the Circle of Willis, brain capillary density, heart rate, or arterial blood gases of db/db mice. The eNOS SD mutation, but not the SA mutation, lowers blood pressure and improves vascular reactivity to acetylcholine in db/db mice. The eNOS SD mutation reduces stroke size and neurological deficit after middle cerebral artery occlusion.


Diminished eNOS phosphorylation is a mechanism of vascular dysfunction in db/db mice. We show here that modulation of the eNOS S1176 phosphorylation site in db/db mice is associated with improved vascular reactivity and improved outcome to stroke after middle cerebral artery occlusion.


diabetes mellitus; endothelial cells; nitric oxide

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