Endothelial dysfunction in small arteries and early signs  of atherosclerosis in ApoE knockout rats

Abstract

Endothelial dysfunction is recognized as a major contributor to atherosclerosis and has been suggested to be evident far before plaque formation. Endothelial dysfunction in small resistance arteries has been suggested to initiate long before changes in conduit arteries. In this study, we address early changes in endothelial function of atherosclerosis prone rats. Male ApoE knockout (KO) rats (11- to 13-weeks-old) were subjected to either a Western or standard diet. The diet intervention continued for a period of 20–24 weeks. Endothelial function of pulmonary and mesenteric arteries was examined in vitro using an isometric myograph. We found that Western diet decreased the contribution of cyclooxygenase (COX) to control the vascular tone of both pulmonary and mesenteric arteries. These changes were associated with early stage atherosclerosis and elevated level of plasma total cholesterol, LDL and triglyceride in ApoE KO rats. Chondroid-transformed smooth muscle cells, calcifications, macrophages accumulation and foam cells were also observed in the aortic arch from ApoE KO rats fed Western diet. The ApoE KO rats are a new model to study endothelial dysfunction during the earlier stages of atherosclerosis and could help us improve preclinical drug development.

Extensive Simulated Diving Aggravates Endothelial Dysfunction in Male Pro-atherosclerotic ApoE Knockout Rats

“…This might also be the case at the basal endothelial activity state in our rats. A previous study on ApoE KO rats also showed changes in COX-dependent signaling and increased endothelium-dependent contraction in pulmonary arteries of ApoE KO rats (Berenji Ardestani et al, 2020). In this study, incubation of pulmonary arteries with indomethacin and L-NAME made no difference in neither contractile or relaxation responses between the two groups.…”

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“…In this study, incubation of pulmonary arteries with indomethacin and L-NAME made no difference in neither contractile or relaxation responses between the two groups. The difference in the present result, compared to the previous (Berenji Ardestani et al, 2020), could be due to the lower extent of hypercholesteremia in this current study; rats were fed a Western diet for a period of 8 weeks and total plasma cholesterol level was much lower (7.8 mmol/L) compared to the previous study (36.43 mmol/L). Accordingly, it is possible that the extent of oxidative stress was less (Berenji Ardestani et al, 2019).…”

“…Although we believe the last possibility is most probable, a clear answer will await further investigation. A similar result was reported earlier in mesenteric arteries of ApoE KO rats on a Western diet (Berenji Ardestani et al, 2020). ACh-induced responses in the presence of different endothelium-dependent relaxation blockers in mesenteric artery were similar to those found in pulmonary arteries (Supplementary Figures S5, S6), confirming the elevated contribution of NO in endothelium-dependent relaxation in the non-diving group.…”

“…However, large individual and intra-individual variability exists for tolerance to oxygen toxicity, bubble production and DCS risk; the same dive protocol can cause DCS in some individuals and no symptoms in others (Bakovic et al, 2008;Lautridou et al, 2017). Body mass and adipose tissue are associated with DCS risk in both human and rats (Carturan et al, 2002;Buzzacott et al, 2016;Cialoni et al, 2017), and ApoE KO rats have higher body mass and plasma cholesterol levels than Sprague Dawley rats of similar age (Berenji Ardestani et al, 2020). However, since all other rats survived the diving interventions without any observed bubbles or DCS, it is unlikely that hypercholesteremia or heavy body mass were the reason for the significant amount of bubbles in the dead rat.…”

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“…However, Apolipoprotein E knock-out (ApoE KO) animals have emerged as a reliable model to assess the early development of endothelial dysfunction in atherosclerotic disease (Getz and Reardon, 2012;Wei et al, 2015;Rune et al, 2018;Lee et al, 2019). In a previous study, we have shown that male ApoE KO rats develop signs of pro-atherosclerotic changes when fed a high-fat western diet (Berenji Ardestani et al, 2020).…”