Differential regulation of endothelium behavior by progesterone and medroxyprogesterone acetate

Abstract

Medroxyprogesterone acetate (MPA) is a synthetic progestin commonly used in hormone replacement therapy (HRT). The aim of this research was to study and compare the effect of progesterone (Pg) and MPA on the regulation of cellular events associated with vascular homeostasis and disease. Platelet adhesion to endothelial cells (ECs), nitric oxide (NO) production, and cell migration were studied using murine ECs in vitro exposed to the progestins. After 7 min of treatment, MPA significantly inhibited NO synthesis with respect to control values; meanwhile, Pg markedly increased vasoactive production. In senile ECs, the stimulatory action of Pg decreases; meanwhile, MPA maintained its ability to inhibit NO synthesis. The presence of RU486 antagonized the action of each steroid. When ECs were preincubated with PD98059 (MAPK inhibitor) or chelerythrine (protein kinase C (PKC) inhibitor) before Pg or MPA treatment, the former totally suppressed the steroid action, but the PKC antagonist did not affect NO production. In the presence of a PI3K inhibitor (LY294002), a partial reduction in Pg effect and a reversal of MPA action were detected. Using indomethacin, the contribution of the cyclooxygenase (COX) pathway was also detected. On platelet adhesion assays, Pg inhibited and MPA stimulated platelet adhesion to ECs. Under inflammatory conditions, Pg prevented platelet adhesion induced by lipopolysaccharide (LPS); meanwhile, MPA potentiated the stimulatory action of LPS. Finally, although both steroids enhanced migration of ECs, MPA exhibited a greater effect. In conclusion, the data presented in this research provide evidence of a differential regulation of vascular function by Pg and MPA.

Progesterone-Based Therapy Protects Against Influenza by Promoting Lung Repair and Recovery in Females

“…Progesterone induces repair of epithelial cells in the endometrium and myelin fibers in the central nervous system [ 44 , 45 ]. This repair of myelin fibers by P4 [ 46 ] is one factor mediating how this reproductive hormone mitigates the progression of multiple sclerosis [ 29 ].…”

Solving the Puzzle: What Is the Role of Progestogens in Neovascularization?

“…Pablo et al found that P4 promotes nitric oxide (NO) synthesis, EC viability and tube formation, whereas MPA exerts an opposite effect. Irreversible NOS inhibitor significantly reduces P4-induced NO production, and blocking PR partially represses both P4- and MPA-mediated actions; the same inhibitory effect was observed after the treatment of MAPK and PI3K inhibitor [ 31 , 83 ], implying NOS and its related signaling pathways are involved in vessel development. It is not unusual for studies to find discrepancy between the biologic effects of P4 and MPA, with Simoncini et al finding P4-mediated PR promotes the production of NO and endothelial NOS via ERK/Akt phosphorylation, while MPA has an opposite effect.…”

“…Due to the different structures among progestogens, altering molecular biofunctions makes natural P4 and synthetic progestins work in individual patterns. Many papers have revealed drug-specific influences: P4 mainly upregulates VEGF in the basal layers of epithelial cells, while the effect of MPA is primarily exerted on stromal and epithelial cells [ 156 ]; P4 modulates vascular remodeling by inducing VEGF and endothelial NOS, while the regulation of MPA mainly depends on platelet activation [ 31 , 83 ]. Progestins were proved to have a different regulatory intensity for the same angiogenic factor [ 148 ].…”

“…It is not unusual for studies to find discrepancy between the biologic effects of P4 and MPA, with Simoncini et al finding P4-mediated PR promotes the production of NO and endothelial NOS via ERK/Akt phosphorylation, while MPA has an opposite effect. They further verified that P4 and PR antagonist convey no effect on E2-induced NO and endothelial NOS expression, while MPA significantly interferes with E2 actions, suggesting that MPA exerts an inhibitory effect independent of PR [ 83 , 84 ]. A later study confirmed that blocking the glucocorticoid receptor can attenuate the inhibitory effect of MPA [ 85 ].…”

Progesterone promotes endothelial nitric oxide synthase expression through enhancing nuclear progesterone receptor-SP-1 formation

“…Several hormone replacement therapy trials have observed that medroxyprogesterone acetate (MPA) treatment could increase risk of coronary disease and stroke (14,34). Unlike natural progesterone, MPA, as a synthetic progesterone, contains androgen activity (6). In addition, progesterone may act antagonistically to estrogen in menopausal hormone treatments because there exists competition with hormone receptors and other coregulators for binding to essential sites on the promoter (39).…”