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

Area of Science:

• Cardiovascular Research
• Neuroscience
• Endocrinology

Background:

• Diabetes mellitus is linked to reduced endothelial nitric oxide synthase (eNOS) phosphorylation.
• This reduction impairs vascular function and may worsen stroke outcomes.

Purpose of the Study:

• To investigate if modulating eNOS phosphorylation can reverse diabetic vascular dysfunction.
• To determine if eNOS phosphorylation changes improve stroke outcomes in a diabetic mouse model.

Main Methods:

• Utilized db/db mice (type 2 diabetes) crossed with eNOS knock-in mice carrying phosphomimetic (SD) or unphosphorylatable (SA) mutations at the S1176 site.
• Assessed vascular anatomy, physiological parameters, vascular reactivity, and stroke outcomes (infarct volume, neurological deficits) using middle cerebral artery occlusion.

Main Results:

• db/db mice exhibited decreased eNOS phosphorylation at S1176.
• The phosphomimetic SD mutation, but not the SA mutation, lowered blood pressure, enhanced acetylcholine-induced vasodilation, and reduced stroke infarct size and neurological deficits.
• Neither mutation altered Circle of Willis anatomy, brain capillary density, heart rate, or blood gases.

Conclusions:

• Reduced eNOS phosphorylation contributes to vascular dysfunction in diabetic mice.
• Targeting the eNOS S1176 phosphorylation site can improve vascular reactivity and stroke outcomes in diabetes.