Endothelium dysfunction in hind limb arteries of male Zucker Diabetic-Sprague Dawley rats

Endothelium dysfunction produces peripheral vascular disease comorbidities in type 2 diabetes, including hypertension, and critical limb ischemia. In this study we aimed to test endothelial dysfunction, the vasodilator effects of a proteinase-activated receptor 2 (PAR2) agonist (2fLIGRLO), and thromboxane A₂ synthase inhibitor (ozagrel) on PAR2 vasodilation in hind limb arteries ex vivo, using Zucker Diabetic-Sprague Dawley (ZDSD) rats, a model of type 2 diabetes. Male Sprague Dawley rats (SD) and ZDSD were fed a high-fat content 'Western diet' from 16 to 20 weeks of age (wks) then fed a standard laboratory diet. We identified diabetic ZDSD rats by two consecutive blood glucose measurements > 12.5 mM, based on weekly monitoring. We used acetylcholine, 2fLIGRLO, and nitroprusside with wire-myograph methods to compare relaxations of femoral, and saphenous arteries from diabetic ZDSD (21-23 wks) to age-matched normoglycemic SD. All arteries showed evidence of endothelium dysfunction using acetylcholine (reduced maximum relaxations, reduced sensitivity), and higher sensitivities to 2fLIGRLO, and nitroprusside in ZDSD vs SD. Ozagrel treatment of ZDSD distal segments, and end-branches of saphenous arteries decreased their sensitivities to 2fLIGRLO. We tested aortas for altered expression of endothelium-specific gene targets using PCR array and qPCR. PAR2, and placental growth factor gene transcripts were 1.5, and 4-times higher in ZDSD than SD aortas. Hind limb arteries of ZDSD exhibit endothelium dysfunction having less GPCR agonist induced vasodilation by endothelial NO-release. Different expression of several endothelial genes in ZDSD vs SD aortas, including PAR2, suggests altered inflammatory, and angiogenesis signaling pathways in the endothelium of ZDSD.