Abstract
Preeclampsia (PE) is a leading cause of maternal and perinatal morbidity in the U.S. While the pathogenesis remains unclear, PE is characterized by new onset hypertension associated with progesterone deficiency, elevated cytolytic natural killer cells (cNK), inflammation, and endothelial dysfunction. Progesterone is essential in the initiation and maintenance of pregnancy. We have shown that progesterone supplementation regulates endothelial function and suppresses endothelin-1 (ET-1) and stimulates nitric oxide (NO) in response to placental ischemia during pregnancy. In addition, progesterone signals the synthesis and release of progesterone induced blocking factor (PIBF) from lymphocytes in order to regulate the proinflammatory balance of early pregnancy. However the role of PIBF in PE pathology is not well examined. This study was designed to test the hypothesis that inhibition of PIBF causes inflammation and increases markers of endothelial dysfunction and hypertension during pregnancy. Rabbit anti-PIBF IgG (0.25, low dose-LD or 0.50 mg/mL, high dose-HD) was administered intraperitoneal on gestation day (GD) 15 to normal pregnant Sprague Dawley (NP) rats, on GD 18 carotid catheters were inserted and on GD 19 blood pressure (MAP) and samples were collected. MAP in NP rats (n=7) was 99 + 3 mmHg, which increased to 116 + 2 in NP+ anti-PIBF LD (n =10) and 113 + 4 mmHg in NP+ anti-PIBF HD (n=6), p<0.05. Plasma TNF-alpha levels were 35 + 8 pg/mL in NP rats and increased to 84 + 21 pg/mL in NP+ Anti-PIBF HD (n=4), p<0.05. Circulating total NK cells were 67 + 11 in NP rats (n=4), which decreased to 36 + 4 in NP+ Anti-PIBF HD however, cytolytic NK cells were 0.6 + 0.2 in NP which were increased to 3.0 + 1 in NP+ Anti-PIBF HD, p<0.05. Importantly, circulating NO levels were 44 + 11 μM in NP rats (n=5), which significantly decreased to 21 + 1 μM in NP+ Anti-PIBF (n=6) HD, p<0.05. Moreover, renal cortex PPET-1 levels increased 15 fold in NP+ Anti-PIBF (n=6) HD compared to NP rats (n=5). Our study demonstrates that PIBF blockade causes hypertension and inflammation and signs of endothelial dysfunction, all of which are associated with PE, thus indicating the importance of progesterone signaling pathways during healthy pregnancy.
Published Version
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