Cardiovascular Research Advance Access [Accepted Manuscript] published online on January 30, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp038
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Endogenous testosterone attenuates neointima formation after moderate coronary balloon injury in male swine
1 Department of Biomedical Sciences, University of Missouri, Columbia, Missouri, USA
2 Research Cath Laboratory, Center for Gender Physiology and Environmental Adaptation, University of Missouri, Columbia, Missouri, USA
3 Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
4 Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri, USA
* Address for correspondence: D. K. Bowles, Ph.D. E102 Veterinary Medicine University of Missouri Columbia, MO 65211 FAX: 573-884-6890 PHONE: 573-882-7193 Email:BowlesD{at}missouri.edu
Aims: Previous studies from our lab have demonstrated that testosterone increases coronary smooth muscle protein kinase C delta (PKC
) both in vivo and in vitro and inhibits coronary smooth muscle proliferation by inducing Go/G1 cell cycle arrest in a PKC
-dependent manner. The purpose of the present study was to determine whether endogenous testosterone limits coronary neointima formation in a porcine model of post-angioplasty restenosis.
Methods: Sexually mature, male Yucatan miniature swine were either left intact (IM), castrated (CM) or castrated with testosterone replacement (CMT; Androgel, 10 mg/day). Angioplasty was performed in both the left anterior descending and left circumflex coronary arteries with balloon catheter overinflation to induce either moderate (1.25–1.3 x diameter; 3 x 30 sec) or severe (1.4 x diameter; 3 x 30 sec) injury, and animals were allowed to recover for either 10 or 28 days. Injured coronary sections were dissected, fixed, stained (Verheoff-Van Gieson, Ki67, PKC, p27) and analyzed. Vessels without internal elastic laminal rupture were excluded.
Results: Following moderate injury, intimal area, intima to media ratio (I/M) and I/M normalized to rupture index (RI) were increased in CM compared to IM and CMT. RI, medial area, and intimal/medial thickness (IMT) were not different between groups. Neointima formation was inversely related to serum testosterone concentration. Conversely, following severe injury, there were no significant differences between the groups. Testosterone inhibited proliferation and stimulated PKC and p27kip1 expression during neointima formation (10 days post-injury).
Conclusions: These findings demonstrate that endogenous testosterone limits coronary neointima formation in male swine and provides support for a protective role for testosterone in coronary vasculoproliferative diseases such as restenosis and atherosclerosis.
KEYWORDS coronary; vascular smooth muscle; testosterone; angioplasty; restenosis; porcine
Time for primary review: 31 Days