PMID- 23088810 OWN - NLM STAT- MEDLINE DCOM- 20130906 LR - 20161125 IS - 1615-5947 (Electronic) IS - 0890-5096 (Linking) VI - 27 IP - 3 DP - 2013 Apr TI - Effect of hormone replacement therapy in matrix metalloproteinase expression and intimal hyperplasia development after vascular injury. PG - 337-45 LID - S0890-5096(12)00332-9 [pii] LID - 10.1016/j.avsg.2012.05.010 [doi] AB - BACKGROUND: Postmenopausal women taking hormone replacement therapy (HRT) require secondary intervention after vascular reconstruction more frequently than women not taking HRT, often due to increased development of intimal hyperplasia (IH). Matrix metalloproteinases (MMPs) play a role in IH by degradation and remodeling of components of the vascular basement membrane. The MMP pathway is regulated by a balance between MMPs, membrane-type MMPs (MT-MMPs), and tissue inhibitor of MMPs (TIMPs). We have recently provided evidence for unbalanced regulation of the MT1-MMP/MMP-2 pathway in vascular smooth muscle cells (VSMCs) exposed to hormones in vitro. Herein we study the role of HRT in the development of IH in a postmenopausal rodent model of vascular injury and in the modulation of this MMP regulatory pathway in vivo. METHODS: Female rats were aged to 12 months. Animals were ovariectomized (OVX) and 4 weeks later hormones or placebo was delivered via a 90-day slow-release pellet. After 6 weeks of HRT each rat underwent balloon angioplasty of the left common carotid artery. At 14 days postinjury tissue samples were collected and stained with trichrome elastin and for isoform-specific MMPs. RESULTS: After vascular injury, the intima:media (I:M) ratio was decreased in OVX rats receiving placebos as compared with non-OVX controls (P < 0.05). In OVX animals receiving HRT, estrogen with and without progesterone and progesterone alone slightly increased I:M ratio compared with placebo, although no significant difference was found in any HRT group. Injury-induced intimal expression of MMP-2 and -9 was decreased in OVX placebo animals compared with non-OVX controls (P < 0.05). MMP-2 and -9 levels were subsequently increased by each type of hormone therapy compared with placebo, with a significant increase in MMP-9 in response to estrogen with and without progesterone (P < 0.05). Conversely, TIMP-2 was decreased by estrogen compared with placebo (P < 0.05). There was no effect on intimal MT1-MMP in any group. CONCLUSIONS: In this study we detected a statistically significant decrease in IH as a result of OVX. Subsequent HRT exposure resulted in increased I:M ratios compared with OVX animals given placebo, although significance was not reached with the doses given. Long-term exogenous exposure may have a more deleterious effect compared with acute exposure and should be examined further. We also demonstrated a significant reduction in MMP-2 and -9 and TIMP-2 in response to OVX. Subsequent hormone exposure resulted in the upregulation of MMP-2 and -9 without a counterregulatory increase in TIMP, indicating that HRT modulates the MMP regulatory pathway in vivo. The data suggest that the lack of hormones after OVX protects against pathologic remodeling in our aged model of disease and that exposure to both natural and exogenous hormones could be a negative risk factor resulting in an exaggerated vascular response to injury. Future studies should focus on in vivo manipulation of unbalanced MMP regulation for prevention of IH in response to HRT and in general. Furthermore, the age-associated difference in response to the presence of natural hormones in young vs aged models should be investigated. CI - Copyright (c) 2013 Elsevier Inc. All rights reserved. FAU - Mountain, Deidra J H AU - Mountain DJ AD - Department of Surgery, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, USA. FAU - Freeman, Michael B AU - Freeman MB FAU - Kirkpatrick, Stacy S AU - Kirkpatrick SS FAU - Cook, Richard B AU - Cook RB FAU - Chalk, James E AU - Chalk JE FAU - Stevens, Scott L AU - Stevens SL FAU - Goldman, Mitchell H AU - Goldman MH FAU - Grandas, Oscar H AU - Grandas OH LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20121023 PL - Netherlands TA - Ann Vasc Surg JT - Annals of vascular surgery JID - 8703941 RN - 0 (Drug Implants) RN - 0 (Estrogens) RN - 127497-59-0 (Tissue Inhibitor of Metalloproteinase-2) RN - 4G7DS2Q64Y (Progesterone) RN - EC 3.4.24.24 (Matrix Metalloproteinase 2) RN - EC 3.4.24.24 (Mmp2 protein, rat) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - EC 3.4.24.35 (Mmp9 protein, rat) RN - EC 3.4.24.80 (Matrix Metalloproteinase 14) SB - IM MH - Angioplasty, Balloon MH - Animals MH - Carotid Artery Injuries/enzymology/*etiology/pathology MH - Carotid Artery, Common/*drug effects/enzymology/pathology MH - Disease Models, Animal MH - Drug Implants MH - Estrogen Replacement Therapy/*adverse effects MH - Estrogens/*administration & dosage MH - Female MH - Hyperplasia MH - Matrix Metalloproteinase 14/metabolism MH - Matrix Metalloproteinase 2/*metabolism MH - Matrix Metalloproteinase 9/*metabolism MH - *Neointima MH - Ovariectomy MH - Progesterone/*administration & dosage MH - Rats MH - Rats, Sprague-Dawley MH - Time Factors MH - Tissue Inhibitor of Metalloproteinase-2/metabolism MH - Vascular System Injuries/enzymology/*etiology/pathology EDAT- 2012/10/24 06:00 MHDA- 2013/09/07 06:00 CRDT- 2012/10/24 06:00 PHST- 2011/10/07 00:00 [received] PHST- 2012/05/24 00:00 [revised] PHST- 2012/05/29 00:00 [accepted] PHST- 2012/10/24 06:00 [entrez] PHST- 2012/10/24 06:00 [pubmed] PHST- 2013/09/07 06:00 [medline] AID - S0890-5096(12)00332-9 [pii] AID - 10.1016/j.avsg.2012.05.010 [doi] PST - ppublish SO - Ann Vasc Surg. 2013 Apr;27(3):337-45. doi: 10.1016/j.avsg.2012.05.010. Epub 2012 Oct 23.