Persistent insulin signaling coupled with restricted PI3K activation causes insulin-induced vasoconstriction
T Dylan Olver1, Zachary I Grunewald2,3, Thaysa Ghiarone3
1Department of Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatchewan, Canada.
American Journal of Physiology. Heart and Circulatory Physiology
|October 12, 2019
Summary
Insulin can cause harmful vasoconstriction when PI3K is blocked, leading to increased MAPK/ET-1 activity. This study reveals insulin-induced vasoconstriction as a pathological event linked to impaired PI3K signaling.
Area of Science:
- Vascular biology
- Endocrinology
- Metabolic syndrome
Background:
- Insulin influences blood vessel tone via vasodilator and vasoconstrictor pathways.
- Obesity is linked to altered insulin signaling and vascular dysfunction.
Purpose of the Study:
- To investigate if insulin-induced vasoconstriction is pathological.
- To determine the roles of persistent insulin signaling, phosphatidylinositol-3 kinase (PI3K) suppression, and mitogen-activated protein kinase (MAPK)/endothelin-1 (ET-1) activity in this phenomenon.
Main Methods:
- Analysis of existing data on lower-limb blood flow during glucose tolerance tests in lean and obese individuals.
- Experiments with isolated resistance arteries from obese subjects and pigs.
- Pharmacological inhibition of ET-1 receptors, PI3K, and MAPK pathways.
Main Results:
- Obese subjects exhibited greater postprandial vascular resistance compared to lean subjects.
- Insulin-induced vasoconstriction in obese subjects' arteries was reduced by ET-1 receptor antagonism.
- In pigs, prolonged insulin stimulation with PI3K suppression induced vasoconstriction, which was reversed by MAPK inhibition or ET-1 antagonism.
Conclusions:
- Insulin-induced vasoconstriction is a pathological process.
- Impaired PI3K activation, coupled with sustained insulin signaling, drives MAPK/ET-1-dependent vasoconstriction.
- This mechanism contributes to vascular dysfunction in conditions like obesity.
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