Role of endoplasmic reticulum stress and thrombosis in type 2 diabetes‐induced vascular dysfunction

Abstract

Endoplasmic reticulum (ER) stress and thrombosis are important mechanisms that underlie many of the serious consequences of type 2 diabetes. However, the interaction between the ER stress and thrombosis in diabetes‐induced endothelial dysfunction remains unknown. Ten‐weeks‐old type 2 diabetic mice (db‐/db‐) and their controls (db‐/db+) treated with or without the ER stress inhibitor (tauroursodeoxycholic acid, TUDCA, 150 mg/kg per day, for 2 weeks) were used to determine the in vivo contribution of ER stress in vascular dysfunction. Blood pressure was similar in all groups of mice. Blood glucose and body weight were reduced in (db‐/db‐) mice treated with TUDCA. The impaired endothelium‐dependent relaxation (EDR), in response to acetylcholine, in (db‐/db‐) mice was restored after treatment with TUDCA in both aorta and mesenteric resistance arteries (MRA). Additionally, ER stress markers (CHOP and ATF4), NADPH oxidase activity and the mRNA levels of Nox2 and Nox4, which were increased in MRA and aorta from (db‐/db‐) mice, were significantly reduced after TUDCA treatment. Moreover, the vasoconstriction to thrombin and the mRNA levels of thrombin receptor (PAR1) were increased only in MRA from (db‐/db‐) mice and reduced after treatment with TUDCA.This study unveiled novel role of ER stress in the regulation of thrombin signaling and therefore vascular dysfunction in type 2 diabetes.