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 α- and β-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.
|Number of pages||6|
|Journal||Arteriosclerosis, Thrombosis, and Vascular Biology|
|Publication status||Published - 2001|
- Catechol estrogens
- Vascular remodeling