Mild hyper‐caloric intake is associated with peri‐vascular adipose inflammation and vascular dysfunction: modulation by antidiabetic drugs
Authors: Khatib Mohammed Abdel‐Wahed , Sleiman Fatima , Saad Evan Ibrahim , Fouad Hosny H. , Issa Khodr , Eid Ali , Eid Assaad , El‐Yazbi Ahmed F. 
Published: June 2021

Diabetes remains a main risk factor for cardiovascular disorders. The vascular impact of diabetes is typically related to poor glycemic control. Yet, a significant proportion of diabetic patients present with microvascular complications at initial diagnosis, implicating a vascular insult early in the course of metabolic dysfunction. On the other hand, recent evidence suggests that some anti‐diabetic drugs might have a positive impact on diabetic cardiovascular complications apart from their hypoglycemic effect. The mechanism of the early insult occurring in the context of diabetes development is not well‐defined. Furthermore, the potential corrective mechanism of anti‐diabetic drugs was not properly investigated in these circumstances. To address these questions, we developed a high calorie diet (HC)‐fed rat model with delayed development of hyperglycemia. Twelve weeks of feeding were not associated with an increase in neither body weight, blood pressure, blood glucose level, nor plasma insulin levels. Yet, HC‐fed rats showed an increased sensitivity to the pressor effect of phenylephrine together with an increased vascular contractile response evident in aortic segments and mesenteric micro‐vessels. This increased contractility was resistant to calcium‐free physiological solutions implicating a potential upregulation of calcium sensitization mechanisms. This observation was supported functionally whereby the isolated vessel segments showed an increased dependence on Rho‐associated kinase (ROCK) for the induced contraction. While there was no detected increase in ROCK expression, western blotting for phosphorylated MYPT1 showed an increased basal activity in vessels from HC‐fed rats. This was associated with an elevated level of reactive oxygen species as detected by DHE staining. We believe that these abnormalities are brought around by increased TGF‐b expression as a consequence of peri‐vascular adipose tissue inflammation. TGF‐b and Smad3 staining were increased in vascular tissue from HC fed rats. This was also coupled with a reduction and an elevation of AMPK and Erk1/2 phosphorylation, respectively. Furthermore, TGF‐b and IL‐1b mRNA levels were elevated, together with observed areas of macrophage infiltration, in the peri‐vascular adipose tissue dissected from these vessel segments. A detrimental systemic response to HC feeding was ruled out, since there was no increase in neither serum TGF‐b nor advanced glycated end products. Oral treatment with metformin or pioglitazone for the last two weeks of feeding; or switching to normal diet for the same duration were associated with a decrease in markers of adipose inflammation and a reversal of all functional and molecular abnormalities observed in HC‐fed rats. As such, it is likely that early vascular dysfunction in the course of diabetes results as a consequence of peri‐vascular adipose inflammation and could potentially be modified at the early stage by anti‐diabetic drugs with known anti‐inflammatory potential.Support or Funding InformationSupported by AUB MPP fund #320148This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.