Effect of Testosterone on Plaque Development and Androgen Receptor Expression in the Arterial Vessel Wall

Abstract

Background-Recent studies have suggested that testosterone has a protective effect in the arterial vascular system. However, little is known about the molecular aspects of the mechanism(s) involved in these processes. The aim of the present study was to investigate the effect of testosterone on neointimal plaque development and on the expression of the vascular androgen receptor. Methods and Results-Neointimal plaque formation was induced by endothelial denudation in the aortas of male New Zealand White rabbits. Aortic ring segments were cultured for 21 days after endothelial denudation. Testosterone was applied to the culture medium in different doses. Compared with the non-hormone-treated control group, a significant inhibition of neointimal plaque development (expressed as the intima/media ratio) was found at testosterone concentrations of 10 ng/mL (Pϭ0.037) and 100 ng/mL (Pϭ0.012; intima/media ratios: median of controls, 0.25; median of 10 ng/mL testosterone group, 0.15; median of 100 ng/mL testosterone group, 0.16). Associated with this inhibitory effect on plaque size was a 50% increase of the amount of androgen receptor mRNA in the arterial segments treated with testosterone. Conclusion-The beneficial effects of testosterone on postinjury plaque development underlines, at least in males, the important role of androgens in the vascular system. As our data suggest, the vascular androgen receptor is probably involved in these processes. Further studies are required to characterize the androgen receptor-dependent pathways in the vascular system. Key Words: testosterone Ⅲ receptors, androgen Ⅲ atherosclerosis T he role of androgens in atherogenesis is controversial 1 ; however, in recent years, several authors have found a number of beneficial effects of testosterone, at least in men. Animal studies have documented an inhibitory effect on plaque development in the cholesterol-fed rabbit model, 2,3 whereas in recent clinical investigations, acute hemodynamic effects of testosterone on coronary vasomotion and stress-test induced ischemia were observed. 4,5 Thus far, only limited information is available regarding the possible involvement of arterial androgen receptors in these processes. Thus, the aim of the present study was to investigate, in an experimental model, (1) the dose-dependent effects of testosterone on plaque development, (2) the expression of the androgen receptor in arteries, and (3) possible dose-dependent changes of androgen receptor expression induced by testosterone. Methods Organ Culture SystemTwelve-week-old male New Zealand White rabbits were used for the present study. The rabbits received standard chow without cholesterol (Altromin Inc) and were housed individually (no female rabbits were present). After sacrifice, the abdomen was opened under sterile conditions, and the connective tissue was removed from the aorta. A 3F-Fogarty catheter (Baxter Inc) was inserted below the iliac bifurcation, and endothelial denudation was performed once with the inflated catheter. The aorta was then comp...

Long-term benefits of testosterone replacement therapy on angina threshold and atheroma in men

“…In follow-up studies, those patients with a low testosterone blood level had bigger changes in CIMT over time, representing increased atheroma progression (19,20). Prospective animal studies are consistent with this and have shown that physiological androgen replacement inhibits atheroma progression (11,(21)(22)(23). There are currently no in vivo human data on the effects of androgen therapy on atheroma.…”

Hormonal effects on blood vessels

“…Many, but not all, of the previous studies indicated that testosterone might inhibit VSMC growth. Hanke et al 113 reported, using an ex vivo organ culture system, that testosterone at 10-100 ng ml -1 significantly inhibited neointima formation in association with increased expression of AR in endothelium-denuded rabbit aortic rings after 21 days of incubation. Somjen et al 114 demonstrated the dose-dependent inhibitory effects of dihydrotestosterone and membrane-impermeable testosterone on DNA synthesis in cultured VSMCs derived from the human umbilical artery, suggesting a role for membrane AR.…”

Effects of androgens on cardiovascular remodeling

“…Low testosterone level is also associated with poor vasodilation of the brachial artery and is an independent risk factor for endothelial dysfunction in men (Akishita et al 2007). Androgen replacement has been shown to prevent aortic atherosclerotic changes in castrated male rabbits fed a high cholesterol diet (Alexandersen et al 1999), and arterial AR mRNA upregulation by testosterone has been shown to reduce neointimal plaque formation in male rabbits (Hanke et al 2001). Endogenous testosterone also inhibits coronary neointimal formation after balloon injury through enhanced expression of PKC d and p27 (kip1; Tharp et al 2009).…”