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

Abstract

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.

Vitamin D supplementation improves pathophysiology in a rat model of preeclampsia

“…Endothelial dysfunction is an observed pathological event in the RUPP model, evident by vascular impairment, reductions in nitric oxide (NO) bioavailability, and production of ET-1 (3,13,32,37,40). Interestingly, we did not observe a change in circulating nitric oxide (NO) levels in RUPP rats treated with VD.…”

Increased risk for the development of preeclampsia in obese pregnancies: weighing in on the mechanisms

“…Studies using the RUPP rat model of placental ischemia have shown that placental ischemia/hypoxia stimulates production of soluble inflammatory and anti-angiogenic placental factors that are capable of entering into the maternal circulation where they target the endothelium. These factors cause vascular dysfunction by reducing nitric oxide (NO) bioavailability and increasing ET-1 production (36,83). Endothelial dysfunction has been detected in obese pregnancies.…”

Polymorphisms in Sex Hormone Metabolism Genes and Risk of Preeclampsia in Taiyuan, China

“…Furthermore, estradiol and its metabolites influence blood pressure through inhibiting the renin-angiotensin system [17][18][19][20]. Studies reported that circulating progesterone was decreased in PE patients [15]. The gradual decrease in sex hormone levels with increasing severity of PE suggests an impairment of placental steroidogenesis [8].…”

“…Progesterone can inhibit tumor necrosis factor-alpha-induced endothelin-1 secretion, which can damage vascular endothelium resulting in poorly perfused fetoplacental unit in PE [15,16]. Progesterone metabolites have also been shown to act as an anti-inflammatory factor that relieve hypertension and decrease inflammatory cytokines [15]. Furthermore, estradiol and its metabolites influence blood pressure through inhibiting the renin-angiotensin system [17][18][19][20].…”

“…Pregnancies with PE showed a chronic inflammatory response, resulting in an increase in the release of inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6 into the placenta and circulation [7]. Progesterone can inhibit tumor necrosis factor-alpha-induced endothelin-1 secretion, which can damage vascular endothelium resulting in poorly perfused fetoplacental unit in PE [15,16]. Progesterone metabolites have also been shown to act as an anti-inflammatory factor that relieve hypertension and decrease inflammatory cytokines [15].…”