TY - JOUR
T1 - Methoxyestradiols mediate the antimitogenic effects of estradiol on vascular smooth muscle cells via estrogen receptor-independent mechanisms
AU - Dubey, Raghvendra K.
AU - Gillespie, Delbert G.
AU - Zacharia, Lefteris C.
AU - Rosselli, Marinella
AU - Korzekwa, Kenneth R.
AU - Fingerle, Juergen
AU - Jackson, Edwin K.
PY - 2000/11/11
Y1 - 2000/11/11
N2 - Estrogen receptors (ERs) are widely held to mediate the ability of 17β-estradiol (estradiol) to attenuate injury-induced proliferation of vascular smooth muscle cells (VSMCs) leading to vascular lesions. However, recent findings that estradiol prevents injury-induced vascular lesion formation in knockout mice lacking either ERα or ERβ seriously challenge this concept. Here we report that the local metabolism of estradiol to methoxyestradiols, endogenous metabolites of estradiol with no affinity for ERs, is responsible for the ER-independent inhibitory effects of locally applied estradiol on rat VSMC growth. These finding imply that local vascular estradiol metabolism may be an important determinant of the cardiovascular protective effects of circulating estradiol. Thus, interindividual differences, either genetic or acquired, in the vascular metabolism of estradiol may define a given female's risk of cardiovascular disease and influence the cardiovascular benefit she receives from estradiol replacement therapy in the postmenopausal state. These findings also imply that nonfeminizing estradiol metabolites may confer cardiovascular protection in both women and men. (C) 2000 Academic Press.
AB - Estrogen receptors (ERs) are widely held to mediate the ability of 17β-estradiol (estradiol) to attenuate injury-induced proliferation of vascular smooth muscle cells (VSMCs) leading to vascular lesions. However, recent findings that estradiol prevents injury-induced vascular lesion formation in knockout mice lacking either ERα or ERβ seriously challenge this concept. Here we report that the local metabolism of estradiol to methoxyestradiols, endogenous metabolites of estradiol with no affinity for ERs, is responsible for the ER-independent inhibitory effects of locally applied estradiol on rat VSMC growth. These finding imply that local vascular estradiol metabolism may be an important determinant of the cardiovascular protective effects of circulating estradiol. Thus, interindividual differences, either genetic or acquired, in the vascular metabolism of estradiol may define a given female's risk of cardiovascular disease and influence the cardiovascular benefit she receives from estradiol replacement therapy in the postmenopausal state. These findings also imply that nonfeminizing estradiol metabolites may confer cardiovascular protection in both women and men. (C) 2000 Academic Press.
KW - Cardiovascular disease
KW - Hormone replacement therapy
KW - Menopause
KW - Metabolism
KW - Vascular remodeling
UR - http://www.scopus.com/inward/record.url?scp=0034638620&partnerID=8YFLogxK
U2 - 10.1006/bbrc.2000.3755
DO - 10.1006/bbrc.2000.3755
M3 - Article
C2 - 11071850
AN - SCOPUS:0034638620
SN - 0006-291X
VL - 278
SP - 27
EP - 33
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 1
ER -