PC228. Testosterone Replacement Attenuates Hyperplasia Development in an Androgen-Deficient Model of Vascular Injury Independent of Matrix Metalloproteinase Regulation

Abstract

Clinical and epidemiologic studies have shown low testosterone (TST) is associated with increased risk of vascular disease, yet the molecular mechanisms remain unclear. Matrix metalloproteinases (MMPs) are implicated in dysfunctional remodeling. Our group has previously demonstrated an inverse relationship between TST levels and MMP activity in vitro. We have also demonstrated androgen deficiency (AD)-modulated inflammatory signaling does not influence systemic MMPs in vivo. Here we investigated the role of AD and TST replacement in MMP-modulated remodeling in response to injury. Subphysiological and physiological TST replacement was administered via implanted pellets in aged orchiectomized rats (0.5-5 mg, Table I). Serum TST was determined by enzyme-linked immunosorbent assay. At 14 days, TST replacement rats underwent balloon angioplasty of the left common carotid. Young intact (YI), aged intact (AI), and orchiectomized placebo (Plac) animals served as controls. Carotids were collected 14 days after injury for intima:media (I:M) and MMP quantification. I:M was increased in Plac, sub-physiological, and low-physiological TST animals compared with AI controls (Fig 1) but was decreased with higher physiological TST. Injury-induced expression of MMPs involved in vascular remodeling was not significantly affected by TST status (Table II). AD increased IH development in response to vascular injury while physiological TST replacement attenuated this effect. This attenuation occurs independent of MMP mechanisms known to be heavily involved in vascular remodeling. Future in vivo studies will examine AD and TST replacement in the acute inflammatory response to vascular injury to delineate additional molecular targets. These studies are needed in determining if TST replacement therapy in AD men should be evaluated for attenuation of vascular pathogenesis.Table ISerum TST levels (ng/mL)Baseline14-day post-TSTControlsYI3.82 ± 0.864.38 ± 0.93ControlsAI2.04 ± 0.442.24 ± 0.54Plac0.62 ± 0.210.18 ± 0.02Sub-physiologic0.5 mg0.30 ± 0.040,65 ± 0.04Physiologic2.5 mg0.38 ± 0.082.24 ± 0.37Physiologic5 mg0.63 ± 0.263.87 ± 0.48AI, Aged intact; TST, testosterone; YI, young intact. Open table in a new tab Table II% Intima stainedMMP-2 regulatory pathwayMMP-9 regulatory pathwayMT1-MMPMMP-2TIMP-2MMP-9TIMP-1YI4.2 ± 1.117.5 ± 7.215.8 ± 6.311.7 ± 5.21.3 ± 0.6AI10.0 ± 5.029.6 ± 5.913.3 ± 4.58.5 ± 2.22.0 ± 0.6Plac3.8 ± 1.222.0 ± 6.711.8 ± 5.49.8 ± 2.81.9 ± 0.80.5 mg8.7 ± 3.523.8 ± 3.118.5 ± 5.717.4 ± 4.22.7 ± 0.62.5 mg11.2 ± 4.020.0 ± 4.210.7 ± 3.212.8 ± 2.93.0 ± 0.95 mg9.9 ± 2.930.1 ± 3.211.7 ± 2.023.7 ± 6.63.6 ± 0.6AI, Aged intact; MMP, matrix metalloproteinase; MT1-MMP, membrane type 1-matrix metalloproteinase 1; YI, young intact.P = not significant, n = 5.7. Open table in a new tab