Previous reports suggest that diabetes may differentially affect the vascular beds of females and males. The objectives of this study were to examine whether there were (1) sex differences in aortic function and (2) alterations in the relative contribution of endothelium-derived relaxing factors in modulating aortic reactivity in UC Davis Type 2 Diabetes Mellitus (UCD-T2DM) rats. Endothelium-dependent vasorelaxation (EDV) in response to acetylcholine (ACh) was measured in aortic rings before and after exposure to pharmacological inhibitors. Relaxation responses to sodium nitroprusside were assessed in endothelium-denuded rings. Moreover, contractile responses to phenylephrine (PE) were measured before and after incubation of aortic rings with a nitric oxide synthase (NOS) inhibitor in the presence of indomethacin. Metabolic parameters and expression of molecules associated with vascular and insulin signaling as well as reactive oxygen species generation were determined. Diabetes slightly but significantly impaired EDV in response to ACh in aortas from females but potentiated the relaxation response in males. The potentiation of EDV in diabetic male aortas was accompanied by a traces of nitric oxide (NO)- and prostanoid-independent relaxation and elevated aortic expression of small- and intermediate conductance Ca2+-activated K+ channels in this group. The smooth muscle sensitivity to NO was not altered, whereas the responsiveness to PE was significantly enhanced in aortas of diabetic groups in both sexes. Endothelium-derived NO during smooth muscle contraction, as assessed by the potentiation of the response to PE after NOS inhibition, was reduced in aortas of diabetic rats regardless of sex. Accordingly, decreases in pAkt and peNOS were observed in aortas from diabetic rats in both sexes compared with controls. Our data suggest that a decrease in insulin sensitivity via pAkt-peNOS-dependent signaling and an increase in oxidative stress may contribute to the elevated contractile responses observed in diabetic aortas in both sexes. This study demonstrates that aortic function in UCD-T2DM rats is altered in both sexes. Here, we provide the first evidence of sexual dimorphism in aortic relaxation in UCD-T2DM rats.
Diving seals are repeatedly exposed to hypoxia‐reoxygenation and other pro‐inflammatory stimuli such as shear stresses in alveoli from lung collapse and re‐expansion. Moreover, they have a known hyperlipidemic status, which is associated with vascular inflammatory stress in humans and mice. To investigate potential protective strategies in free‐living populations of deep‐diving seals, we examined baseline levels of cytokine biomarkers, as well as the inflammatory response of IL6 gene expression in seal blood cells exposed to an endotoxin (LPS, lipopolysaccharide, 1–1000ng/mL). Despite aspects of their basic physiology that predisposes other mammals to inflammatory stress, cytokine production in healthy Weddell seals (adults and pups) and Northern elephant seals (adults only) following LPS incubation was blunted (10–100X increase in plasma IL6), compared to human samples assayed under the same conditions (>1000X increase). These plasma samples, further assayed using a cytokine panel validated for pinnipeds, revealed that many cytokines were below detectable levels in Weddell seals, with only IL6, IL10 and TNFα exhibiting a dose‐response to LPS. Under isolated, in vitro conditions, Weddell seal monocytes maintained the expected, robust response to stimulation with LPS endotoxin. However, when this response was compared under typical cell culture conditions (using media supplemented with FBS) versus media supplemented with an equivalent amount of Weddell seal serum (WSS), IL6 expression from stimulated monocytes exposed to WSS declined significantly (LPS dose*serum‐type 2way repeated‐measures ANOVA across all doses: F1,6= 8.5, p=0.027 for FBS vs WSS), as did cytokines detected in the cell culture media. To further elucidate the potential anti‐inflammatory properties of seal serum, we repeated the experiment comparing FBS to de‐complemented WSS in RAW cells, a mouse macrophage line. These results validated our findings from seal monocytes, demonstrating that mouse cytokine expression (IL6, TNFα, and Mcp1), was consistently reduced in cells cultured with WSS compared to FBS. Finally, we confirmed that these results held in RAW cells exposed to other TLR ligands, including Pam‐3‐Cys, Poly I:C and CpG DNA (TNFα expression in WSS<FBS, p=0.0001 in each experiment). These findings suggest that seal serum innately possesses anti‐inflammatory properties, which may protect these deep divers from naturally occurring inflammatory challenges such as dive‐induced hypoxia‐reoxygenation and lung collapse.Support or Funding InformationFunded by the National Science Foundation (Office of Polar Programs).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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