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Effects in Postmenopausal Women of Estradiol and Medroxyprogesterone Alone and Combined on Resistance Artery Function and Endothelial Morphology and Movement

Department of Clinical Science (K.K., E.S., B.-M.L.), Intervention and Technology, Section for Obstetrics and Gynecology, Karolinska Institute, Karolinska University Hospital-Huddinge Campus, 14186 Stockholm, Sweden; and Molecular and Cellular Gynecological Endocrinology Laboratory (X.-D.F., A.R.G., T.S.), Department of Reproductive Medicine and Child Development, University of Pisa, 56100, Pisa, Italy

Address all correspondence and requests for reprints to: Karolina Kublickiene, M.D., Ph.D., Department of Clinical Science, Intervention and Technology, Section for Obstetrics and Gynecology, Karolinska Institute, Karolinska University Hospital-Huddinge Campus, 14186 Stockholm, Sweden. E-mail: karolina.kublickiene{at}ki.se; or Tommaso Simoncini, M.D., Ph.D., Molecular and Cellular Gynecological Endocrinology Laboratory, Department of Reproductive Medicine and Child Development, University of Pisa, Via Roma, 67, 56100, Pisa, Italy. E-mail: t.simoncini{at}obgyn.med.unipi.it.

Context: Endothelial dysfunction in resistance arteries after menopause is important for the development of high blood pressure and cardiovascular disease.

Objectives: Our objectives were to study the effects of different hormone replacement therapies on the function and morphology of isolated resistance arteries, and to look for their mechanistic basis.

Design and Setting: This was a randomized, placebo-controlled double-blind study in a University hospital, along with laboratory based studies.

Patients and Interventions: We isolated resistance arteries in sc biopsies from 55 postmenopausal women before and after 3-month therapy with estradiol (E2), medroxyprogesterone acetate (MPA), E2 plus MPA, or placebo. In addition, we studied isolated human endothelial cells.

Main Outcome Measures and Results: Artery flow-mediated dilatation was augmented after treatment with E2 or E2 plus MPA, whereas MPA or placebo had no effect. Pressure-induced myogenic tone was reduced by E2 plus MPA, whereas it was unchanged in the other groups. Scanning microscopy showed that E2 improved endothelial cell morphology and decreased signs of endothelial apoptosis, but the addition of MPA impaired these events. E2, MPA, or the combination all increased the expression and phosphorylation of the actin-binding protein, moesin and of the focal adhesion complex controller, focal adhesion kinase, and induced the rearrangement of cytoskeletal actin and vinculin fibers. All treatments promoted endothelial cell horizontal migration, with E2 inducing the strongest effect.

Conclusions: This study suggests that hormone replacement therapy with estrogens or in combination with MPA may benefit the function of resistance arteries and may preserve the morphological integrity of endothelial cells by regulatory actions on the cytoskeleton.

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