Abstract 284: Testosterone Replacement Attenuates Hyperplasia Development in an Androgen Deficient Model of Vascular Injury Independent of Matrix Metalloproteinase Regulation

Abstract

Objectives: Clinical and epidemiological 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. Methods: Sub-physiological and physiological TST replacement was administered via implanted pellets in aged orchiectomized rats (0.5-5mg, Table 1). Serum TST was determined by ELISA. At 14d 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 14d post-injury for intima:media (I:M) and MMP quantification. Results: I:M was increased in Plac, sub-, and low-physiological TST animals compared to AI controls, and decreased with higher physiological TST (Fig 1). Injury-induced expression of MMPs involved in vascular remodeling was not significantly affected by TST status (Table 2). Conclusions: AD is associated with hyperplasia 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 molecular targets involved in AD and the effect of TST replacement in the acute inflammatory response to vascular injury. These studies are needed in determining if TST replacement therapy in AD men should be evaluated for attenuation of vascular pathogenesis.