Androgen exposure increases human monocyte adhesion to vascular endothelium and endothelial cell expression of vascular cell adhesion molecule-1

Heart Research Institute, Departments of Cardiology and Andrology, Royal Prince Alfred Hospital, Sydney, Australia.
Circulation (Impact Factor: 14.43). 06/1999; 99(17):2317-22. DOI: 10.1161/01.CIR.99.17.2317
Source: PubMed


Male sex is an independent risk factor for coronary artery disease. Owing to the importance of monocyte adhesion to endothelial cells in the development of atherosclerosis, we hypothesized that androgens might promote this process. We therefore studied the effects of the nonaromatizable androgen dihydrotestosterone (DHT) on human monocyte adhesion to human endothelial cells and on endothelial cell-surface expression of adhesion molecules.
Human umbilical vein endothelial cells (HUVECs) were grown to confluence in media supplemented with postmenopausal female serum, then exposed for 48 hours to either DHT (40 and 400 nmol/L), with or without the androgen receptor blocker hydroxyflutamide (HF) (4 micromol/L); HF alone; or vehicle control (ethanol 0.1%). Human monocytes obtained by elutriation were incubated for 1 hour with the HUVECs at 37 degrees C, and adhesion was measured by light microscopy. Compared with vehicle control, monocyte adhesion was increased in the androgen-treated HUVECs in a dose-dependent manner (116+/-6% and 128+/-3% for DHT 40 and 400 nmol/L respectively; P<0.001). HF blocked this increase (P>/=0.3 compared with control). Surface expression of endothelial cell adhesion molecules was measured by ELISA and revealed an increased expression of vascular cell adhesion molecule-1 (VCAM-1) in the DHT-treated HUVECs (125+/-5% versus 100+/-4% in controls; P=0.002), an effect also antagonized by HF (P>/=0.3 compared with controls). Furthermore, the DHT-related increase in adhesion was completely blocked by coincubation with anti-VCAM-1 antibody. Comparable results were obtained in arterial endothelial cells and in endothelium stimulated with the cytokine tumor necrosis factor-alpha.
Androgen exposure is associated with increased human monocyte adhesion to endothelial cells, a proatherogenic effect mediated at least in part by an increased endothelial cell-surface expression of VCAM-1.

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    • "As male sex is one of the major risk factors for the development of cardiovascular disease, it is hypothesized that androgens promote atherosclerosis. In fact, several in vivo and in vitro studies have suggested that androgens increase expression of proatherogenic factors (Adams et al. 1995, McCrohon et al. 1999, Ng et al. 2003, Nheu et al. 2011). In contrast, recent clinical studies have shown that low endogenous testosterone levels are associated with advanced atherosclerosis of the carotid artery in middleaged males and that this association is independent of the traditional cardiovascular risk factors (Muller et al. 2004, Makinen et al. 2005). "
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    ABSTRACT: Androgens, the male sex hormones, exert various biological effects on many target organs through the transcriptional effects of the nuclear androgen receptor (AR). ARs are expressed not only in classical target organs, such as the brain, genital organs, bone, and skeletal muscles, but also in the cardiovascular system. Because the female sex hormones estrogens are well-known to protect against cardiovascular disease, sex has been considered to have a significant clinical impact on cardiovascular mortality. However, the influence of androgens on the cardiovascular system has not been fully elucidated. To clarify this issue, we analyzed the effects of administration of angiotensin II and doxorubicin, an anticancer agent, in a loading model in male wild-type and AR-deficient mice. In this review, we focus on the actions of androgens as potential targets for the prevention of cardiovascular diseases in males.
    Journal of Endocrinology 04/2012; 214(1):1-10. DOI:10.1530/JOE-12-0126 · 3.72 Impact Factor
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    • "Leukostasis is positively influenced by the expression of ICAM and VCAM-1 with androgens and estrogens modulating expression of these attachment proteins. The upregulation of these proteins by DHT has been blocked by the androgen receptor blocker hydroxyflutamide (McCrohon et al. 1999). Estrogens inhibited ICAM and VCAM-1 expression (Cid et al. 1994; Simoncini et al. 1999; Villablanca et al. 2010). "

    Diabetic Retinopathy, 02/2012; , ISBN: 978-953-51-0044-7
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    • "ion increased ET - 1 to a greater extent in women with PCOS than in controls ( 3 . 68 versus 7 . 10 fmol ml −1 for control and PCOS , respectively , following methyl testosterone administration ) ( Stachenfeld et al . 2010 ) . Although a number of studies have demonstrated testosterone exposure may be involved in endothelial dysfunction in women ( McCrohon et al . 1999 ; Orio et al . 2004 ) , other studies have failed to demonstrate this relationship ( Mather et al . 2000 ) . Nonetheless , there is evidence to suggest that the hyperandrogenic state in PCOS is a risk factor for the development of early endothelial dysfunction ( Orio et al . 2004 ) . Endothelin - 1 is lowest in the later follicular and "
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    ABSTRACT: Non-Technical Summary Although the core feature in polycystic ovary syndrome (PCOS) is a hormonal imbalance, this syndrome is associated with obesity, insulin resistance, hypertension and endothelial dysfunction. This constellation of factors leads to greater risks for infertility, diabetes and cardiovascular disease. In this study we examine two important receptors involved in endothelial function, ET-A and ET-B, using the skin microcirculation to examine small blood vessel responses. We demonstrate that the ET-B receptor is likely to play an important role in the pathophysiology of cardiovascular disease in women with PCOS. Abstract Endothelin-1 is elevated in women with polycystic ovary syndrome (PCOS), and may play a role in the endothelial dysfunction associated with PCOS. Endothelin-1 binds two receptor subtypes, endothelin A (ET-A) and endothelin B (ET-B). We hypothesized that ET-A mediates vasoconstriction in the cutaneous microvasculature in women with and without PCOS. We further hypothesized that while the ET-B receptors mediate vasodilatation in both groups of women, this response would be blunted in women with PCOS. During local skin warming, we used laser Doppler flowmetry combined with intradermal microdialysis to measure skin blood flow (SkBF) during graded ET-A (BQ-123) and ET-B (BQ-788) antagonist infusions in women with (n= 6) and without (n= 8) PCOS. In both groups, SkBF increased during local heating. The percentage of maximal SkBF–[BQ123] sigmoidal dose–response curve indicated a vasodilatory response as the concentration of the antagonist increased (Hill slope 4.96 ± 4.77, 4.74 ± 5.01; logED50 2.53 ± 0.09, 2.49 ± 0.09 nm, for PCOS and Control, respectively). In contrast, the % max SkBF–[BQ788] curve indicated a vasoconstrictive response (Hill slope –4.69 ± 3.85, –4.03 ± 3.85; logED50, 2.56 ± 0.09, 2.41 ± 0.12 nm, in PCOS and Control). Moreover, the SkBF–[BQ788] curve shifted to the right in women with PCOS, suggesting attenuated ET-B receptor mediated vasodilatation during local skin warming compared to Controls. Thus, the endothelium located ET-B receptors function similarly in women with and without PCOS, although with blunted responsiveness in women with PCOS. Our studies suggest that the lower ET-B receptor responsiveness associated with PCOS may reflect lower endothelial-mediated vasodilatation independent of generally lower vascular reactivity.
    The Journal of Physiology 08/2011; 589(Pt 19):4671-9. DOI:10.1113/jphysiol.2011.216218 · 5.04 Impact Factor
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