Since the initial isolation of aldosterone in 1953 and the cloning of the mineralocorticoid receptor (MR) decades later, our understanding has expanded tremendously regarding their involvement in the pathogenesis of CVD. Recent results from both pre-clinical and clinical studies support a close correlation between increase adiposity and enhanced aldosterone production (MR activation). Importantly, insulin resistance and obese females are more prone to the deleterious cardiovascular effects of MR activation, and enhanced MR activation in females has emerged as an important causative event in the genesis of a more severe CVD in diabetic women. Different clinical trials have been completed examining the effect of MR blockade in subjects with CVD. Despite its important beneficial mortality impact, side effects are frequent and a newer MR antagonist, finerenone, with less risk of hyperkalemia is currently being tested in large clinical trials.
Arterial stiffening, a characteristic feature of type 2 diabetes, is an important contributor to the development and progression of cardiovascular disease (CVD). Thus, a better understanding of the precipitating factors underlying arterial stiffening is vital to identify newer targets and strategies to reduce CVD burden, particularly in diabetic women who exhibit heightened arterial stiffening and more severe CVD. Degradation of the endothelial glycocalyx in diabetes is thought to contribute to endothelial dysfunction and CVD development. However, whether glycocalyx degradation is also an important determinant of arterial stiffening remains unknown. Herein, we hypothesize that restoration of the glycocalyx with dietary supplementation of glycocalyx precursors (DSGP, including glucosamine sulfate, fucoidan, superoxide dismutase, and high molecular weight hyaluronan; Endocalyx TM ) improves endothelial function and lessens arterial stiffness in diabetic female mice. To test this hypothesis, we used 12-week old db/db female mice that were treated with DSGP (100 mg/kg/day) or vehicle ( i.e. , peanut butter) for four weeks, and an age-matched db/+ cohort as reference control. After euthanasia, we assessed ex vivo aortic stiffness and glycocalyx length via atomic force microscopy. Using pressure myography, we also determined ex vivo mesenteric artery endothelial function and stiffness by measuring flow-mediated dilation and the passive mechanical properties of the arterial wall, respectively. Consistent with our hypothesis, vehicle-treated db/db mice exhibited degradation of the endothelial glycocalyx, impaired endothelium-dependent vasodilation, and increased arterial stiffness when compared with control db/+ females. Moreover, treatment with DSGP was effective at restoring the endothelial glycocalyx in db/db mice. Notably, this restoration of the glycocalyx was accompanied with improvements in endothelial function and reductions in arterial stiffness. Collectively, these findings support the notion that the endothelial glycocalyx should be considered as a putative therapeutic target to reverse arterial stiffening in diabetic females.
Background Repetitive hypoxic apneas, similar to what is observed in sleep apnea, result in resetting of the sympathetic baroreflex to higher blood pressures (BP) in humans. This resetting of the baroreflex is associated with increased BP in preclinical models of sleep apnea (chronic intermittent hypoxia, CIH); however, the majority of our understanding comes from men. There are data to suggest female rats exposed to CIH do not develop high BP. With this, we sought to examine potential sex‐related differences in the effect of intermittent hypoxia (IH) on the sympathetic baroreflex. We hypothesized young men would exhibit resetting of the baroreflex to higher BP following IH, with no change in young women. Methods BP and muscle sympathetic nerve activity (MSNA) were assessed in 17 men (30±1 yrs) and 10 women (28±1 yrs) during quiet normoxic rest prior to and following 30‐min of experimental IH [30‐s hypoxic exposures (0.05 FiO2) alternating with 90‐s room air breathing] resulting in 15 hypoxic events (91.7±0.5 % SpO2). Sympathetic baroreflex sensitivity was evaluated using the modified Oxford technique before and after 30‐min of IH. Results Diastolic BP increased in men following IH (71±2 to 74±2 mmHg; p<0.01) with no change in women (75±3 to 75±3 mmHg; p=0.97). Sympathetic baroreflex sensitivity did not change following IH in either group (Men: −1.8±0.2 to −1.9±0.3; Women: −1.6±0.3 to −2.1± 0.5 bursts/100 heart beats/mmHg; Main effect of IH, p=0.14; Interaction of group and IH, p=0.28). Conclusion Acute IH resets the sympathetic baroreflex to higher BP in young men, with no change in young women. Baroreflex sensitivity slopes were unchanged in either group following IH. Our results support sex differences in the effect of IH on sympathetic control of BP and show that young women are protected from the BP‐raising effects of IH. These data enhance our understanding of sex‐specific mechanisms that may contribute to the development of hypertension in sleep apnea. Support or Funding Information NIH HL130339, Mayo Clinic Center for Biomedical Discovery
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