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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1745.)
© 2001 American Heart Association, Inc.

Vascular Biology

Catecholamines Abrogate Antimitogenic Effects of 2-Hydroxyestradiol on Human Aortic Vascular Smooth Muscle Cells

Lefteris C. Zacharia; Edwin K. Jackson; Delbert G. Gillespie; Raghvendra K. Dubey

From the Center for Clinical Pharmacology (L.C.Z., E.K.J., D.G.G., R.K.D.), Departments of Medicine (E.K.J., D.G.G., R.K.D.) and Pharmacology (L.C.Z., E.K.J.), University of Pittsburgh Medical Center, Pittsburgh, Pa, and the Clinic for Endocrinology (R.K.D.), Department of Obstetrics and Gynecology, University Hospital Zurich, Zurich, Switzerland.

Correspondence to Dr Raghvendra K. Dubey, D217, NORD-1, Clinic for Endocrinology, Department of Obstetrics and Gynecology, Frauenklinik, Zurich 8091, Switzerland. E-mail rag{at}fhk.usz.ch

Abstract—— Catechol-O-methyltransferase (COMT)-mediated methylation of 2-hydroxyestradiol (endogenous estradiol metabolite) to 2-methoxyestradiol (angiogenesis inhibitor) may be responsible for the antimitogenic effects of 2-hydroxyestradiol on vascular smooth muscle cells (VSMCs). Catecholamines are also substrates for COMT, and increased levels of catecholamines are associated with vasoocclusive disorders. We hypothesize that catecholamines may abrogate the vasoprotective effects of 2-hydroxyestradiol by competing for COMT and inhibiting 2-methoxyestradiol formation. To test this hypothesis, we investigated the antimitogenic effects of 0.001 to 0.1 µmol/L of 2-hydroxyestradiol on human aortic VSMC proliferation (cell number and DNA synthesis), collagen synthesis, and migration in the presence and absence of catecholamines. Norepinephrine, epinephrine, and isoproterenol concentration-dependently abrogated the inhibitory effects of 2-hydroxyestradiol on cell number, DNA synthesis, collagen synthesis, and cell migration. These modulatory/attenuating effects of catecholamines were not abrogated in the presence of the - and ß-adrenergic receptor antagonists, phentolamine mesylate and propranolol, respectively. In contrast to 2-hydroxyestradiol, the antimitogenic effects of 2-methoxyestradiol (0.1 µmol/L) were not attenuated by isoproterenol (1 µmol/L) or quercetin (competitive inhibitor of COMT, 10 µmol/L). Norepinephrine, epinephrine, and isoproterenol concentration-dependently (10 to 500 µmol/L) inhibited the metabolism of 2-hydroxyestradiol (0.25 to 2 µmol/L) to 2-methoxyestradiol, and the potency of the catecholamines to reverse 2-hydroxyestradiol-induced inhibition of VSMC proliferation, collagen synthesis, and migration was correlated with their ability to inhibit 2-methoxyestradiol formation. Our findings suggest that catecholamines within the vasculature may abrogate the anti-vaso-occlusive effects of estradiol and 2-hydroxyestradiol by blocking 2-methoxyestradiol formation.

Key Words: estradiol • catechol estrogens • methoxyestradiol • menopause • vascular remodeling

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