Progesterone blunts vascular endothelial cell secretion of endothelin-1 in response to placental ischemia

• Published in: American journal of obstetrics and gynecology 2013-07, Vol.209 (1), p.44.e1-44.e6
• Main Authors: Kiprono, Luissa V., DO, Wallace, Kedra, PhD, Moseley, Janae, BS, Martin, James, MD, LaMarca, Babbette, PhD
• Format: Article
• Language: English
• Subjects: Animals; Disease Models, Animal; Endothelial Cells - drug effects; Endothelial Cells - metabolism; endothelin; Endothelin-1 - metabolism; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hydroxyprogesterones - pharmacology; Hydroxyprogesterones - therapeutic use; Hypertension - metabolism; Hypertension - physiopathology; Ischemia - metabolism; Ischemia - physiopathology; Obstetrics and Gynecology; Placenta; Placental Circulation - physiology; placental ischemia; Pre-Eclampsia - drug therapy; Pre-Eclampsia - metabolism; preeclampsia; Pregnancy; progesterone; Progesterone - pharmacology; Progesterone - therapeutic use; Progestins - pharmacology; Progestins - therapeutic use; Rats; Rats, Sprague-Dawley
• ISSN: 0002-9378; 1097-6868
• DOI: 10.1016/j.ajog.2013.03.032

Objective Preeclampsia (PE) is associated with hypertension and elevated endothelin (ET-1), an indicator of endothelial cell activation and dysfunction. Reduction of uteroplacental perfusion (RUPP) in the pregnant rat model of PE is characterized by elevated mean arterial pressure, inflammatory cytokines, and activation of the ET-1 system. We aim to determine whether 17-alpha-hydroxyprogesterone caproate (17-OHPC) or progesterone suppresses these pathways. Study Design Plasma progesterone was purified from normal pregnant (NP) and PE patients and measured via enzyme-linked immunosorbent assay. Human umbilical vein endothelial cells were exposed to the sera with or without progesterone added and ET-1 was measured. Pregnant rats underwent the RUPP procedure with or without intraperitoneal 17-OHPC. Mean arterial pressure was compared in RUPP vs NP rats. Human umbilical vein endothelial cells were exposed to NP or RUPP sera, with and without progesterone and ET-1 measured. Results Progesterone was significantly decreased in PE women compared with NP women. In response to human sera, ET-1 was elevated in PE women compared to NP women, and decreased with addition of progesterone. Mean arterial pressure was significantly elevated in RUPP vs NP rats but was attenuated by 17-OHPC. ET-1 secretion was stimulated significantly by RUPP compared to NP rat sera, but attenuated by progesterone. Conclusion Circulating progesterone is significantly lower in PE women compared to controls. 17-OHPC attenuates hypertension in response to placental ischemia in RUPP rats. Progesterone blunts vascular ET-1 stimulated at cellular level by sera from PE women or RUPP rats. Decreased circulating progesterone is associated with stimulation of ET-1. 17-OHPC supplementation blunts hypertension and progesterone blunts endothelial cell ET-1 secretion in response to placental ischemia.