Altered circulating hormone levels, endothelial function and vascular reactivity in the testicular feminished mouse

Abstract

Objective: Testicular feminised (Tfm) mice express a non-functional androgen receptor, and also have reduced levels of circulating testosterone. Recent studies support a cardio-protective role for testosterone since it elicits systemic and pulmonary vasodilatation. The aim of the present study was to determine whether androgen insensitivity and hypotestosteronaemia in the Tfm mouse are associated with abnormal vascular reactivity or hormone status. Methods: Adult male Tfm and littermate control mice were killed and the blood collected. Femoral (diameter range = 183-508 μm) and pulmonary (diameter range = 320-816 μm) arteries were dissected and loaded in either a wire or pressure myograph, at 100 mmHg or 17.5 mmHg respectively. Pharmacological assessment of the vasoreactivity to potassium chloride (KCl, 80 mmol/l) and either noradrenaline (NA, 1 nmol/l-100 μmol/l) and acetylcholine (ACh, 0.1-100 μmol/l) or testosterone (1 nmol/l-100 μmol/l) was then made. Results: Tfm mice had reduced levels of testosterone (1.8±0.3 nmol/l) compared with controls (9.3±2.0 nmol/l, P < 0.001) and elevated levels of cholesterol (3.6+0.1 mmol/l) compared with controls (3.2 + 0.1 mmol/l, P < 0.05). Femoral arteries from Tfm mice exhibited reduced vasoconstriction to 80 mmol/l KCl (3.27±0.23 mN/mm) compared with vessels from controls (4.44±0.41 mN/mm, P < 0.05), and reduced endothelial-dependent vasodilatation to 0.1-100 μmol/l ACh (23.3±3.6% relaxation) compared with vessels from controls (41.6±5.4% relaxation, P < 0.05). Vasoconstriction to NA (1 nmol/l-100 μmol/l) and vasodilatation to testosterone were unaffected. Conclusions: Androgen receptor deficiency and hypotestosteronaemia in the Tfm mouse reduced endothelial function and impaired voltage-operated calcium channel activity, which may pre-dispose to cardiovascular disease. Testosterone-induced vasodilatation was unaffected, demonstrating no involvement of the androgen receptor in this response.