Testosterone replacement attenuates intimal hyperplasia development in an androgen deficient model of vascular injury.

Autor: Freeman BM; Department of Surgery, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee., Univers J; Department of Surgery, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee., Fisher RK; Department of Surgery, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee., Kirkpatrick SS; Department of Surgery, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee., Klein FA; Department of Surgery, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee., Freeman MB; Department of Surgery, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee., Mountain DJ; Department of Surgery, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee., Grandas OH; Department of Surgery, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee. Electronic address: OGrandas@utmck.edu.
Jazyk: angličtina
Zdroj: The Journal of surgical research [J Surg Res] 2017 Jan; Vol. 207, pp. 53-62. Date of Electronic Publication: 2016 Aug 10.
DOI: 10.1016/j.jss.2016.08.016
Abstrakt: Background: Androgen deficiency (AD) is associated with increased risk of vascular disease. Dysfunctional remodeling of the vessel wall and atypical proliferative potential of vascular smooth muscle cells (VSMCs) are fundamental processes in the development of intimal hyperplasia (IH). We have demonstrated an inverse relationship between dihydrotestosterone (DHT) levels, matrix metalloproteinase activity, and VSMC migration and proliferation in vitro. Here, we investigated the role of AD and testosterone (TST) replacement in IH development in an animal model of vascular injury to elucidate mechanisms modulated by AD that could be playing a role in the development of vascular pathogenesis.
Methods: Aged orchiectomized male rats underwent TST supplementation via controlled release pellet (0.5-35 mg). Young adult and middle-age adult intact (MI) and orchiectomized placebo (Plac) groups served as controls. All groups underwent balloon angioplasty of the left common carotid at a 14-d post-TST. Carotid tissue was collected at a 14-d post-balloon angioplasty and subjected to morphologic and immunohistochemical analyses. Human male VSMCs were treated with DHT (0-3000 nM) for 24 h then subjected to quantitative PCR for gene expression analyses and costained for F-actin and G-actin for visualization of cytoskeletal organization.
Results: I:M ratio was increased in Plac, subphysiological, low-physiological, and high pharmacologic level TST animals compared with MI controls but was decreased with high-physiological TST supplementation. Injury-induced expression of previously defined matrix metalloproteinase remodeling enzymes was not significantly affected by TST status. Urotensin (UTS) receptor (UTSR) staining was low in injured vessels of all young adult intact, MI, and Plac controls but was significantly upregulated in all groups receiving exogenous TST supplementation, irrespective of dose. In vitro DHT exposure increased the expression of UTSR in VSMCs in a dose-dependent manner. However, this did not correlate with any change in proliferative markers. F:G actin staining revealed that DHT-induced cytoskeletal organization in a dose-dependent manner.
Conclusions: AD increased IH development in response to vascular injury, whereas physiological TST replacement attenuated this effect. AD-induced IH occurs independent of matrix remodeling mechanisms known to be heavily involved in vascular dysfunction, and AD alone does not affect the UTS and/or UTSR mechanism. Exogenous TST and/or DHT increases UTSR pathway signaling in vitro and in vivo. This modulation correlates to a shift in cytoskeletal organization and may exacerbate vasoconstrictive pathogenesis. While physiological TST replacement attenuates AD-modulated IH development, its UTS-mediated effect on vasotone may prove deleterious to overall vascular function.
(Copyright © 2016 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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