6: Progesterone induced blocking factor inhibition causes inflammation and endothelial dysfunction in pregnant Sprague Dawley rats

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 as well as progesterone deficiency, elevated cytolytic natural killer cells (NK), inflammation, and endothelial dysfunction. Progesterone is essential in the initiation and maintenance of pregnancy. It signals the synthesis and release of progesterone induced blocking factor (PIBF) from lymphocytes that acts through inhibition of NK cells and can regulate the proinflammatory balance which could promote endothelial regulation through suppression of endothelin-1 (ET-1) and stimulation of nitric oxide (NO). However the role of PIBF in PE pathology is not well examined. This study was designed to test the hypothesis that PIBF blockade causes inflammation and increases markers of endothelial dysfunction and hypertension in normal pregnant rats. Rabbit anti-PIBF IgG (0.25, low dose-LD or 0.50 mg/mL, high dose-HD) was administered intraperitoneal on gestation day 15 to normal pregnant Sprague Dawley (NP) rats, on day 18 carotid catheters were inserted and on GD 19 blood pressure 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 in NP+anti-PIBF HD (n=6), p< 0.05. Circulating total NK cells were 67 + 11 in NP rats (n=4), which decreased to 28 + 7 in NP+ Anti-PIBF LD and 36 + 4 in NP+ Anti-PIBF HD. Cytolytic NK cells were 0.6 + 0.2 in NP which were increased to 2.0 + 1 in NP+ Anti-PIBF LD and 3.0 + 1 in NP+ Anti-PIBF HD, p< 0.05. Circulating TNF-alpha levels were increased with PIBF blockade. 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). In conclusion, our study demonstrates that PIBF blockade indeed causes hypertension, inflammation and increased markers of endothelial dysfunction, all of which are associated with PE.