Progestogens reduce thromboxane production by cultured human endothelial cells.
OBJECTIVE
Progestogens have been poorly studied concerning their roles in endothelial physiology. Prostanoids are vasoactive compounds, such as thromboxane A2, a potent vasoconstrictor, and prostacyclin, a vasodilator. We examined the effects of two progestogens used clinically, progesterone and medroxyprogesterone acetate, on thromboxane A2 production by cultured human umbilical vein endothelial cells (HUVEC) and investigated the role of progesterone receptors and the enzymes involved in production of thromboxane A2 and prostacyclin.


METHODS
Cells were exposed to 1-100  nmol/l of either progesterone or medroxyprogesterone acetate, and thromboxane A2 production was measured in culture medium by enzyme immunoassay. Gene expression of prostacyclin synthase and thromboxane synthase was analyzed by quantitative real-time polymerase chain reaction. Expression of prostacyclin synthase protein was analyzed by Western blot.


RESULTS
Both progestogens decreased thromboxane A2 release after 24 h. Protein and gene expression of prostacyclin synthase were increased after exposure to both progestogens, without changes in thromboxane synthase expression. These effects induced by progestogens were mediated through progesterone receptors, since they were decreased in the presence of the progesterone receptor antagonist RU486. The cyclo-oxygenase-1 selective inhibitor reduced thromboxane release.


CONCLUSIONS
Progesterone and medroxyprogesterone acetate decreased HUVEC thromboxane release in a progesterone receptor-dependent manner, without changes in thromboxane synthase expression and enhanced prostacyclin synthase gene and protein expression.
Oviedo
P J
PJ
Research Foundation, Hospital Clínico Universitario, University of Valencia, Valencia, Spain.
Sobrino
A
A
Novella
S
S
Rius
C
C
Laguna-Fernandez
A
A
García-Pérez
M A
MA
Tarín
J J
JJ
Cano
A
A
Hermenegildo
C
C
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism*; D015870:Gene Expression; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D015735:Mifepristone / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011374:Progesterone / Q000494:pharmacology*; D011372:Progestins / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013928:Thromboxane A2 / Q000378:metabolism*; D013929:Thromboxane B2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000235:genetics / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology
D018931:Antineoplastic Agents, Hormonal; D016861:Cyclooxygenase Inhibitors; D006727:Hormone Antagonists; D011372:Progestins; D011720:Pyrazoles; D012333:RNA, Messenger; C115461:SC 560; D015735:Mifepristone; D011374:Progesterone; D013929:Thromboxane B2; D013928:Thromboxane A2; D003577:Cytochrome P-450 Enzyme System; D017258:Medroxyprogesterone Acetate; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D013930:Thromboxane-A Synthase