Pharmacologic inhibition of transient receptor channel vanilloid 4 attenuates abdominal aortic aneurysm formation.

Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, leukocyte infiltration, and vascular remodeling. This study investigates the role of TRPV4 channels, which are transmembrane calcium channels that can regulate vascular tone, in modulating AAA formation. The elastase-treatment model of AAA in C57BL6 (WT) mice and Angiotensin II treatment model in ApoE-/- mice were used to confirm our hypotheses. The administration of a specific TRPV4 antagonist, GSK2193874, in elastase-treated WT mice and in AngII-treated ApoE-/- mice caused a significant attenuation of aortic diameter, decrease in pro-inflammatory cytokines (IL-1ß, IL-6, IL-17, MCP-1, MIP-1α, MIP-2, RANTES, and TNF-α), inflammatory cell infiltration (CD3 + T cells, macrophages, and neutrophils), elastic fiber disruption, and an increase in smooth muscle cell α-actin expression compared to untreated mice. Similarly, elastase-treated TRPV4-/- mice had a significant decrease in AAA formation, aortic inflammation, and vascular remodeling compared to elastase-treated WT mice on Day 14. In vitro studies demonstrated that the inhibition of TRPV4 channels mitigates aortic smooth muscle cell-dependent inflammatory cytokine production as well as decreases neutrophil transmigration through aortic endothelial cells. Therefore, our results suggest that TRPV4 antagonism can attenuate aortic inflammation and remodeling via decreased smooth muscle cell activation and neutrophil transendothelial migration during AAA formation.

Female Mice Exhibit Abdominal Aortic Aneurysm Protection in an Established Rupture Model.

BACKGROUND: Male gender is a well-established risk factor for abdominal aortic aneurysm (AAA), whereas estrogen is hypothesized to play a protective role. Although rupture rates are higher in women, these reasons remain unknown. In the present study, we sought to determine if female mice are protected from AAA rupture. MATERIALS AND METHODS: Apolipoprotein E-deficient male and female mice (aged 7 wk; n = 25 per group) were infused with angiotensin II (AngII; 2000 ng/kg/min) plus ß-aminopropionitrile (BAPN) in the drinking water for 28 d to test the effects of gender on AAA rupture. Separately, a second group of male apolipoprotein E-deficient mice underwent AngII infusion + BAPN while being fed high-fat phytoestrogen free or a high-fat phytoestrogen diet to assess effects of phytoestrogens on rupture. In a third group, female mice either underwent oophorectomy or sham operation 4 wk before infusion of AngII and BAPN to further test the effects of female hormones on AA rupture. Surviving mice abdominal aorta were collected for histology, cytokine array, and gelatin zymography on postoperative day 28. RESULTS: Female mice had decreased AAA rupture rates (16% versus 46%; P = 0.029). Female mice expressed fewer elastin breaks (P = 0.0079) and decreased smooth muscle cell degradation (P = 0.0057). Multiple cytokines were also decreased in the female group. Gelatin zymography demonstrated significantly decreased pro-matrix metalloproteinase 2 in female mice (P = 0.001). Male mice fed a high dose phytoestrogen diet failed to decrease AAA rupture. Female mice undergoing oophorectomy did not have accelerated aortic rupture. CONCLUSIONS: These data are the first to attempt to tease out hormonal effects on AAA rupture and the possible role of gender in rupture.

Sex differences in response to lifestyle intervention among children and adolescents: Systematic review and meta-analysis.

OBJECTIVE: Little is known about sex differences in response to lifestyle interventions among pediatric populations. The purpose of this analysis was to evaluate sex differences in adiposity following lifestyle interventions among children and adolescents with overweight or obesity aged 6 to 18 years old. METHODS: Searches were conducted in PubMed, Web of Science, and MEDLINE (from inception to March 2021), and references from included articles were examined. Eligibility criteria included children and adolescents aged 6 to 18 years with overweight or obesity, randomization to a lifestyle intervention versus a control group, and assessment of at least one adiposity measure. Corresponding authors were contacted to obtain summary statistics by sex (n = 14/49). RESULTS: Of 89 full-text articles reviewed, 49 (55%) were included, of which 33 (67%) reported statistically significant intervention effects on adiposity. Only two studies (4%) evaluated sex differences in response to lifestyle intervention, reporting conflicting results. The results of the meta-regression models demonstrated no significant differences in the treatment effect between male and female youth for weight (beta = -0.05, SE = 0.18, z = -0.28, p = 0.8), BMI (beta = 0.03, SE = 0.14, z = 0.19, p = 0.85), BMI z score (beta = -0.04, SE = 0.18, z = -0.23, p = 0.82), percentage body fat (beta = -0.11, SE = 0.16, z = -0.67, p = 0.51), and waist circumference (beta = -0.30, SE = 0.25, z = -1.18, p = 0.24). CONCLUSIONS: The meta-analysis revealed that youth with overweight or obesity do not demonstrate a differential response to lifestyle intervention in relation to adiposity-related outcomes.