Estrogen deficiency-induced alterations of vascular MMP-2, MT1-MMP, and TIMP-2 in ovariectomized rats.
BACKGROUND
Matrix metalloproteinases (MMPs) activity may modulate hypertension-related accumulation of extracellular matrix (ECM) in arteries. We tested whether estrogen deficiency induces alterations of vascular collagen, MMP-2, membrane-type 1-MMP (MT1-MMP), or tissue inhibitor of metalloproteinases-2 (TIMP-2) expression in ovariectomized rats, which may be associated with postmenopausal hypertension.


METHODS
Estrogen deficiency was induced by ovariectomy (Ovx) in female rats. Time-course changes of aortic MMPs protein expression were evaluated. Treatment with tempol or aminoguanidine was used to examine the role of oxidative stress and nitric oxide (NO) on these changes.


RESULTS
The level of the active-form MMP-2 was markedly reduced during 1-4 weeks after Ovx, with a significant increase in collagen accumulation and increased MT1-MMP expression. Although active-form MMP-2 and collagen progressively returned to normal levels, the markedly increased collagen deposition appeared again at 8 weeks and persisted until 12 weeks, followed by induction of MMP-2 and MT1-MMP at 12 weeks. The TIMP-2 level reduced for 2 weeks after Ovx, but soon returned to normal. Treatment with 17beta-estradiol (E(2)), tempol, or aminoguanidine for 6 weeks prevented Ovx-induced blood pressure elevation and apparently reversed the MMPs changes.


CONCLUSIONS
In an initial period, E(2) deficiency induces a reduction of active-form MMP-2 leading to collagen accumulation, and induction of MT1-MMP, which may be a compensatory response to degrade collagen. At a latter stage, the concurrent elevation of active-form MMP-2 and MT1-MMP expression may be adaptive responses to regulate ECM composition in the vascular wall. Oxidative stress and NO contribute to activity modulation of vascular MMPs in Ovx rats.
Lam
Kwok-Keung
KK
Department of Pharmacology, Taipei Medical University, Taipei, Taiwan.
Cheng
Pao-Yun
PY
Hsiao
George
G
Chen
Shu-Ying
SY
Shen
Hsin-Hsueh
HH
Yen
Mao-Hsiung
MH
Lee
Yen-Mei
YM
D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology* / Q000503:physiopathology; D001794:Blood Pressure / Q000502:physiology; D015153:Blotting, Western; D004195:Disease Models, Animal; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D005500:Follow-Up Studies; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D010052:Ovariectomy / Q000009:adverse effects*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis*; D014655:Vascular Resistance
D004967:Estrogens; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14