Estrogen deficiency modifies matrix metalloproteinases activity and vascular function of mesenteric arteries in female rats

Abstract

Objective: Estrogen possesses vasoprotective effects and its deficiency has been implicated in the pathogenesis of postmenopausal hypertension. Reduced matrix metalloproteinases (MMPs) activity is accompanied with extracellular matrix (ECM) accumulation in large arteries, leading to the hypertensive arterial remodeling in resistance arteries. In the present study, we investigate whether estrogen deficiency induces alteration of MMP-mediated cleavage of vascular collagen in rats with ovariectomy (Ovx). Materials and Methods: Adult female rats were ovariectomized bilaterally to induce estrogen deficiency. Evolution of systolic blood pressure, diastolic blood pressure (DBP), and mean blood pressure (MBP) was monitored weekly until 12 weeks after Ovx in conscious rats. The vascular reactivity and time-course changes of collagen type I, MMP-2, membrane type 1-MMP (MT1-MMP), and tissue inhibitor of metalloproteinase-2 (TIMP-2) protein expression in mesenteric arteries were evaluated. Results: Compared with sham group, DBP and MBP significantly increased 5 weeks after Ovx, lasting to at least 12 weeks. Acetylcholine-induced vasodilatation of precontracted mesenteric rings significantly reduced 9 weeks after Ovx. Collagen type I accumulation in mesenteric arteries appeared 6 weeks after Ovx, which persisted till 12 weeks. The levels of latent and active MMP-2 did not show significant change until 12 weeks after Ovx. Moreover, MT1-MMP significantly downregulated during 1–4 weeks and soon recovered to normal levels. TIMP-2 reduced at 4th week and gradually returned to normal levels during 6–12 weeks. Conclusion: Long-term estrogen deficiency results in a shift in ECM profiles and diminished MMPs activities, leading to remodeling of small arteries, which may be associated with postmenopausal hypertension. This study provides new insight into the pathophysiology of vascular remodeling in estrogen-deficient conditions.

Keywords

• Estrogen
• matrix metalloproteinases
• vascular remodeling
• postmenopausal hypertension