Abstract
AimsLow androgen levels have been linked with an increased risk of cardiovascular disease in men. Previous studies have suggested that androgens directly inhibit atherosclerotic lesion formation although the underlying mechanisms for this remain unclear. This study addressed the hypothesis that endogenous androgens inhibit arterial remodelling by a direct action on the androgen receptor (AR) in the vascular wall.Methods and resultsWe studied a series of novel mouse lines with cell-specific deletion of the AR in either the endothelium or in smooth muscle cells or both cell types. Findings were compared with a model of global androgen deficiency in wild-type mice (castrated). We characterized the cardiovascular phenotype, vascular pharmacology and histology, and assessed neointimal lesion formation following vascular injury to the femoral artery. Cell-specific AR deletion did not alter body weight, circulating testosterone levels or seminal vesicle weight, but caused limited alterations in arterial contractility and blood pressure. Neointimal lesion formation was unaltered by selective deletion of AR from the vascular endothelium, smooth muscle, or both cell types. Castration in wild-type mice increased neointimal lesion volume (Sham vs. Castration: 2.4 × 107 ± 4.5 × 106 vs. 3.9 × 107 ± 4.9 × 106 µm3, P = 0.04, n = 9–10).ConclusionVascular cell-specific AR deletion had no effect on neointimal lesion formation, while low systemic androgen levels adversely affect neointimal lesion size. These findings suggest that the cardio-protective effects of androgens are mediated either by AR outside the vasculature or by AR-independent mechanisms.
Highlights
Male sex hormones have traditionally been linked to the greater risk of cardiovascular disease (CVD) in men.[1,2] this view is increasingly being challenged, with considerable recent evidence that testosterone may, be cardio-protective
SM22-Cre), VE-AR knockout mice (ARKO) (EC ARKO, generated using Tie2-Cre), and SM/VE-ARKO, and floxed-androgen receptor (AR) mice (WT), which were used as controls
In order to confirm deletion of AR in targeted cell types, genomic DNA from freshly isolated aortic Endothelial cell (EC) and Smooth muscle cell (SMC) were subjected to PCR analysis
Summary
Male sex hormones have traditionally been linked to the greater risk of cardiovascular disease (CVD) in men.[1,2] this view is increasingly being challenged, with considerable recent evidence that testosterone may, be cardio-protective. There has been a 10-fold increase in prescribed ART in the USA9 and nearly a 3-fold increase in the UK10 in the past decade. ART improves the muscle/fat mass ratio, bone mineral density, and blood lipid profile[6,11,12] in hypogonadal men. Concerns have been raised about safety and the Food and Drug Administration in the USA has announced an investigation into the risk of stroke, heart attack, and death in men taking testosterone products.[13] This follows recent reports demonstrating an excess of cardiovascular events in apparently
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