Differential signal transduction of progesterone and medroxyprogesterone acetate in human endothelial cells.
The conjugated equine estrogens-only arm of the Women's Health Initiative trial, showing a trend toward protection from heart disease as opposed to women receiving also medroxyprogesterone acetate (MPA), strengthens the debate on the cardiovascular effects of progestins. We compared the effects of progesterone (P) or MPA on the synthesis of nitric oxide and on the expression of leukocyte adhesion molecules, characterizing the signaling events recruited by these compounds. Although P significantly increases nitric oxide synthesis via transcriptional and nontranscriptional mechanisms, MPA is devoid of such effects. Moreover, when used together with physiological estradiol (E2) concentrations, P potentiates E2 effects, whereas MPA impairs E2 signaling. These findings are observed both in isolated human endothelial cells as well as in vivo, in ovariectomized rat aortas. A marked difference in the recruitment of MAPK and phosphatidylinositol-3 kinase explains the divergent effects of the two gestagens. In addition, both P and MPA decrease the adhesiveness of endothelial cells for leukocytes when given alone or with estrogen. MPA is more potent than P in inhibiting the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1. However, when administered together with physiological amounts of glucocorticoids, MPA (which also binds glucocorticoid receptor) markedly interferes with the hydrocortisone-dependent stabilization of the transcription factor nuclear factor kappaB and with the expression of adhesion molecules, acting as a partial glucocorticoid receptor antagonist. Our findings show significant differences in the signal transduction pathways recruited by P and MPA in endothelial cells, which may have relevant clinical implications.
Simoncini
Tommaso
T
Molecular and Cellular Gynecological Endocrinology Laboratory, Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa 56100, Italy. t.simoncini@obgyn.med.unipi.it
Mannella
Paolo
P
Fornari
Letizia
L
Caruso
Antonella
A
Willis
Monica Y
MY
Garibaldi
Silvia
S
Baldacci
Chiara
C
Genazzani
Andrea R
AR
D002450:Cell Communication / Q000187:drug effects; D002478:Cells, Cultured; D003271:Contraceptive Agents, Female / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D006801:Humans; D007962:Leukocytes / Q000166:cytology; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D010052:Ovariectomy; D010766:Phosphorylation; D011374:Progesterone / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects; D014471:Umbilical Veins / Q000166:cytology
D003271:Contraceptive Agents, Female; D009569:Nitric Oxide; D011374:Progesterone; D004958:Estradiol; D017258:Medroxyprogesterone Acetate; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III