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Estrogen and Progesterone Inhibit Vascular Smooth Muscle Proliferation¹

Division of Endocrinology, Long Beach Veteran Affairs Medical Center, Long Beach, California 90822; and Departments of Medicine (A.P., M.R., R.-M.H., E.B., E.R.L.) and Pharmacology (A.K.M., B.A.P., E.R.L.), University of California, Irvine, Irvine, California 92717

Address all correspondence and requests for reprints to: Ellis R. Levin M.D., Medical Service (111-I), Long Beach Veterans’ Hospital, Long Beach, California 90822. E-mail: elevin{at}pop.long-beach.va.gov

Estrogen (E) has been identified in epidemiologic and prospective studies to protect against the development of cardiovascular disease in women. It is unclear whether progesterone (P) is similarly beneficial. The mechanisms by which E or P might act are incompletely defined. One possibility is that sex steroids inhibit the proliferation of vascular smooth muscle, an early/important event in vascular pathology. We examined the ability of E and P to inhibit the growth of human umbilical vein smooth muscle cells (hUVSMC) in culture, when stimulated by serum or the mitogen, endothelin-1(ET-1). Serum and ET-1 stimulated hVSMC cell numbers by approximately 110% and 43% respectively, compared with control, after 3 days in culture. This stimulation was maximally reversed 75% by E and 64% by P. No synergistic or additive effects of the two steroids were found. ET-1 and serum stimulated mitogen-activated protein kinase (MAP-K) and MAP-kinase kinase activities, and these were critical for mitogenesis. Mitogen-stimulated MAP-kinase kinase and MAP-K activities were significantly inhibited by either E or P. The steroids also inhibited mitogen-stimulated c-fos and c-myc, downstream targets for MAP-K action. Critical signaling and molecular events through which mitogens stimulate VSMC proliferation can be significantly inhibited by E or P, providing a potential cellular mechanism for their vascular protective actions.

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