Effects of dietary soy content on cerebral artery function and behavior in ovariectomized female mice.

As females age, they transition through menopause, experiencing a decrease in estrogen and an increase in cardiovascular and neurodegenerative disease risk. Most standard rodent chows contain phytoestrogen-rich soybean meal, which can mimic the effects of estrogen. Understanding the impact of this soybean meal on vascular outcomes is crucial to proper experimental design. Thus, this study aimed to compare the effects of standard and soy-free chows on cerebral artery endothelial function and cognitive function in ovariectomized mice. Young female C57Bl/6J mice (n = 43; ∼6 mo) were randomly assigned to three groups: sham, ovariectomy (OVX), or ovariectomy on a diet containing soy (OVX + Soy). In posterior cerebral arteries, the OVX mice had a 27% lower maximal response to insulin compared with the sham mice. The OVX + Soy mice had a 27% greater maximal vasodilation to insulin compared with the OVX mice and there were no differences in vasodilation between the OVX + Soy and sham groups. The group differences in vasodilation were mediated by differences in nitric oxide bioavailability. The OVX + Soy mice also had greater insulin receptor gene expression in cerebral arteries compared with the OVX mice. However, no differences in aortic or cerebral artery stiffness were observed between groups. Interestingly, the OVX + Soy group scored better on nesting behavior compared with both sham and OVX groups. In summary, we found that ovariectomy impairs insulin-mediated vasodilation in cerebral arteries, but a diet containing soy mitigates these effects. These findings highlight the importance of considering dietary soy when performing vascular and behavioral tests in mice, particularly in females.NEW & NOTEWORTHY To properly design experiments, we must consider how variables like diet impact our outcomes, particularly the effects of soy on females. We found that cerebral artery vasodilation in response to insulin was impaired in ovariectomized female mice compared with intact shams. However, ovariectomized mice fed a soy diet had a preserved cerebral artery insulin-mediated vasodilation. These results highlight that the effects of diet on vascular function may explain inconsistencies found between studies.

AKT Mediates Adiponectin-Dependent Regulation of VSMC Phenotype.

Adiponectin (adipoq), the most abundant hormone in circulation, has many beneficial effects on the cardiovascular system, in part by preserving the contractile phenotype of vascular smooth muscle cells (VSMCs). However, the lack of adiponectin or its receptor and treatment with recombinant adiponectin have shown contradictory effects on plaque in mice. RNA sequence of Adipoq+/+ and adipoq-/- VSMCs from male aortas identified a critical role for adiponectin in AKT signaling, the extracellular matrix (ECM), and TGF-ß signaling. Upregulation of AKT activity mediated proliferation and migration of adipoq-/- cells. Activation of AMPK with metformin or AdipoRon reduced AKT-dependent proliferation and migration of adipoq-/- cells but did not improve the expression of contractile genes. Adiponectin deficiency impaired oxidative phosphorylation (OXPHOS), increased expression of glycolytic enzymes, and elevated mitochondrial reactive oxygen species (ROS) (superoxide, and hydrogen peroxide). Anti-atherogenic mechanisms targeted the ECM in adipoq-/- cells, downregulating MMP2 and 9 and upregulating decorin (DCN) and elastin (ELN). In vivo, the main sex differences in protein expression in aortas involved a more robust upregulation of MMP3 in females than males. Females also showed a reduction in DCN, which was not affected in males. Our study uncovered the AKT/MAPK/TGF-ß network as a central regulator of VSMC phenotype.

Pyridoxamine treatment ameliorates large artery stiffening and cerebral artery endothelial dysfunction in old mice.

Age-related increases in large artery stiffness are associated with cerebrovascular dysfunction and cognitive impairment. Pyridoxamine treatment prevents large artery stiffening with advancing age, but the effects of pyridoxamine treatment on the cerebral vasculature or cognition is unknown. The purpose of this study was to investigate the effects of pyridoxamine on blood pressure, large artery stiffness, cerebral artery function, and cognitive function in old mice. Old male C57BL/6 mice consumed either pyridoxamine (2 g/L) or vehicle control in drinking water for ∼7.5 months and were compared with young male C57BL/6 mice. From pre- to post-treatment, systolic blood pressure increased in old control mice, but was maintained in pyridoxamine treated mice. Large artery stiffness decreased in pyridoxamine-treated mice but was unaffected in control mice. Pyridoxamine-treated mice had greater cerebral artery endothelium-dependent dilation compared with old control mice, and not different from young mice. Old control mice had impaired cognitive function; however, pyridoxamine only partially preserved cognitive function in old mice. In summary, pyridoxamine treatment in old mice prevented age-related increases in blood pressure, reduced large artery stiffness, preserved cerebral artery endothelial function, and partially preserved cognitive function. Taken together, these results suggest that pyridoxamine treatment may limit vascular aging.

The Duality of Adiponectin: The Role of Sex in Atherosclerosis.

The hormone adiponectin has many beneficial effects in atherosclerosis, as gene deficiency in adiponectin or its receptor has shown detrimental effects on plaque burden in mice. Our objective was to understand the potential roles adiponectin deficiency has on aortic plaque content, inflammation, and markers of cardiovascular disease according to sex and age. To study the influence of adiponectin status on sex and atherosclerosis, we used young male and female adipoq-/-apoe-/-, adipoq+/-apoe-/-, and apoe-/- mice, which were given a high-fat diet (HFD). Even a 50% reduction in the expression of adiponectin led to a plaque reduction in males and an increase in females compared with apoe-/- controls. Changes in plaque were not attributed to changes in cholesterol or cardiovascular disease markers but correlated with inflammatory markers. Plaque reduction in males was associated with reduced monocyte chemoattractant protein 1 (MCP1) and increased colony stimulating factor 3 (CSF3), while the increase in plaque in females correlated with the opposite effect in these markers. In old mice, both adiponectin-deficient genotypes and sexes accumulated more plaque than their respective apoe-/- controls. The increase in plaque with adiponectin deficiency according to age was not explained by a worsening lipid profile but correlated with increased levels of C-C motif chemokine ligand 5 (CCL5). Overall, our study uncovered genotype-specific effects that differed by sex and age of adiponectin deficiency in atherosclerosis.

In vivo arterial stiffness, but not isolated artery endothelial function, varies with the mouse estrous cycle.

With the increasing appreciation for sex as a biological variable and the inclusion of female mice in research, it is important to understand the influence of the estrous cycle on physiological function. Sex hormones are known to modulate vascular function, but the effects of the mouse estrous cycle phase on arterial stiffness, endothelial function, and arterial estrogen receptor expression remain unknown. In 23 female C57BL/6 mice (6 mo of age), we determined the estrous cycle stage via vaginal cytology and plasma hormone concentrations. Aortic stiffness, assessed by pulse wave velocity, was lower during the estrus phase compared with diestrus. In ex vivo assessment of isolated pressurized mesenteric and posterior cerebral arteries, the responses to acetylcholine, insulin, and sodium nitroprusside, as well as nitric oxide-mediated dilation, were not different between estrous cycle phases. In the aorta, expression of phosphorylated estrogen receptor-α was higher for mice in estrus compared with mice in proestrus. In the cerebral arteries, gene expression for estrogen receptor-ß (Esr2) was lowest for mice in estrus compared with diestrus and proestrus. These results demonstrate that the estrus phase is associated with lower in vivo large artery stiffness in mice. In contrast, ex vivo resistance artery endothelial function is not different between estrous cycle phases. Estrogen receptor expression is modulated by the estrus cycle in an artery-dependent manner. These results suggest that the estrous cycle phase should be considered when measuring in vivo arterial stiffness in young female mice.NEW & NOTEWORTHY To design rigorous vascular research studies using young female rodents, the influence of the estrous cycle on vascular function must be known. We found that in vivo aortic stiffness was lower during estrus compared with the diestrus phase in female mice. In contrast, ex vivo mesenteric and cerebral artery endothelial function did not differ between estrous cycle stages. These results suggest that the estrous cycle stage should be accounted for when measuring in vivo arterial stiffness.

The Impact of Dietary Supplementation of Whole Foods and Polyphenols on Atherosclerosis.

The purpose of this review is to highlight current research on the benefits of supplementation with foods with a diverse polyphenol composition, including fruits, vegetables, nuts, grains, oils, spices, and teas in blunting atherosclerosis. We searched PubMed for publications utilizing whole food or polyphenols prepared from whole foods in Apolipoprotein E (ApoE) or Low-Density Lipoprotein Receptor (LDLR) knockout mice, and identified 73 studies in which plaque was measured. The majority of the studies reported a reduction in plaque. Nine interventions showed no effect, while three using Agaricus blazei mushroom, HYJA-ri-4 rice variety, and safrole-2', 3'-oxide (SFO) increased plaque. The mechanisms by which atherosclerosis was reduced include improved lipid profile, antioxidant status, and cholesterol clearance, and reduced inflammation. Importantly, not all dietary interventions that reduce plaque showed an improvement in lipid profile. Additionally, we found that, out of 73 studies, only 9 used female mice and only 6 compared both sexes. Only one study compared the two models (LDLR vs. ApoE), showing that the treatment worked in one but not the other. Not all supplementations work in both male and female animals, suggesting that increasing the variety of foods with different polyphenol compositions may be more effective in mitigating atherosclerosis.