The Aortic Function of Female UC Davis Type 2 Diabetes Mellitus (UCD‐T2DM) Rats

Abstract

UC Davis Type 2 Diabetes Mellitus (UCD‐T2DM) rat is a novel validated model of type 2 diabetes mellitus. UCD‐T2DM is characterized by polygenic, adult‐onset obesity and spontaneous β‐cell failure and, as a result, more closely models the pathophysiology of type 2 diabetes in humans than other rodent models. The objectives of this study were to determine the aortic function of female UCD‐T2DM rats and to investigate the underlying mechanism(s) of altered vascular function (if any) in this model. Endothelium‐dependent vasodilation (EDV) to acetylcholine (ACh, 10−8 to 10−5M) was measured in intact aortic rings pre‐contracted with phenylephrine (PE, 2μM). Endothelium‐independent vasodilation to sodium nitroprusside (SNP, 10−9 to 10−5 M) was assessed in endothelium‐denuded rings pre‐contracted with PE (2μM). Furthermore, constrictor response curves to PE (10−8 to 10−5 M) were generated before and after incubation with L‐NAME (200μM), a nitric oxide synthase (NOS) inhibitor. Expression of molecules associated with vascular reactivity and insulin signaling were also evaluated using Western blotting in aortic tissues.We demonstrated that the maximal relaxation to ACh was significantly reduced in aortic rings from female UCD‐T2DM rats compared to controls. The smooth muscle sensitivity to NO as measured by SNP‐induced relaxation was also reduced in this group. The responsiveness to PE was significantly enhanced in aorta of UCD‐T2DM group. Accordingly, the basal nitric oxide (NO), as indicated by the potentiation of the response to PE after L‐NAME, was reduced in diabetes group. Moreover, expression of eNOS, peNOS, pAkt, IRS1 and IRS2 were significantly reduced in the aorta of this disease model.These data, for the first time, show that the vascular function is altered in aortic rings of female UCD‐T2DM rats. Specifically, our data suggests that the decreased sensitivity of vascular smooth muscle to NO along with the enhanced contractile responsiveness to PE may in part contribute to the attenuated ACh responses in aorta of UCD‐T2DM female rats.Support or Funding InformationSupported by NIH/NIHLBIThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.