Abstract
Enhanced mineralocorticoid receptor (MR) signaling is critical to the development of endothelial dysfunction and arterial stiffening. However, there is a lack of knowledge about the role of MR-induced adipose tissue inflammation in the genesis of vascular dysfunction in women. In this study, we hypothesize that MR activation in myeloid cells contributes to angiotensin II (Ang II)-induced aortic stiffening and endothelial dysfunction in females via increased pro-inflammatory (M1) macrophage polarization. Female mice lacking MR in myeloid cells (MyMRKO) were infused with Ang II (500 ng/kg/min) for 4 weeks. This was followed by determinations of aortic stiffness and vasomotor responses, as well as measurements of markers of inflammation and macrophage infiltration/polarization in different adipose tissue compartments. MyMRKO mice were protected against Ang II-induced aortic endothelial stiffening, as assessed via atomic force microscopy in aortic explants, and vasorelaxation dysfunction, as measured by aortic wire myography. In alignment, MyMRKO mice were protected against Ang II-induced macrophage infiltration and M1 polarization in visceral adipose tissue (VAT) and thoracic perivascular adipose tissue (tPVAT). Collectively, this study demonstrates a critical role of MR activation in myeloid cells in the pathogenesis of vascular dysfunction in females associated with pro-inflammatory macrophage polarization in VAT and tPVAT. Our data have potential clinical implications for the prevention and management of cardiovascular disease in women, who are disproportionally at higher risk for poor outcomes.
Highlights
MATERIALS AND METHODSChronic inflammation is invariably present in the setting of cardiovascular disease (CVD) (Saltiel and Olefsky, 2017)
We demonstrate that abrogation of mineralocorticoid receptor (MR) signaling in myeloid cells in female mice protects against the development of aortic stiffening and improves endothelial function, independently of blood pressure changes and vascular smooth muscle relaxation capacity
We show that vascular protection with MR deletion in myeloid cells is associated with a reduction in markers of macrophage infiltration and pro-inflammatory M1 macrophage polarization in thoracic perivascular adipose tissue (tPVAT) and in visceral adipose tissue (VAT)
Summary
Chronic inflammation is invariably present in the setting of cardiovascular disease (CVD) (Saltiel and Olefsky, 2017). We tested the hypothesis that MR activation in myeloid cells mediates aortic stiffening and endothelial dysfunction induced by a continuous infusion of angiotensin II (Ang II) in female mice, and that these vascular effects parallel with changes in adipose tissue macrophage infiltration and pro-inflammatory M1 polarization. A saline-infused MyMRKO cohort was not included in this investigation, as it has been previously reported that these mice do not exhibit phenotypical variations in cardiovascular tissue or macrophage infiltration/polarization under control conditions (Rickard et al, 2009; Usher et al, 2010). Macrophage Infiltration in Visceral Adipose Tissue Formalin-fixed VAT samples were processed through paraffin embedding, sectioned at 5 μm, and stained with macrophage marker Mac-2 antibody (CL8942AP, 1:1,000; Cedarlane, Burlington, ON, CA), as previously described (Winn et al, 2019).
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