Complement activation is critical for placental ischemia-induced hypertension in the rat

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• 作者：Kathryn E. Lillegard^a ; ^{lille067@umn.edu} ; Alex C. Johnson^a ; ^{joh06981@d.umn.edu} ; Sarah J. Lojovich^a ; ^{sarah.lojovich@medtronic.com} ; Ashley J. Bauer^a ; ^{bauer489@d.umn.edu} ; Henry C. Marsh^b ; ^{hmarsh@celldextherapeutics.com} ; Jeffrey S. Gilbert^c ; ^{jgilbe@uoregon.edu} ; Jean F. Regal^a ; ^{jregal@d.umn.edu} ; ^{jregal@umn.edu}
• 关键词：MAP ; mean arterial pressure ; RUPP ; reduced utero-placental perfusion pressure ; sCR1 ; soluble complement receptor 1 ; sFlt-1 ; soluble fms-like tyrosine kinase-1 ; SNP ; sodium nitroprusside ; VEGF ; vascular endothelial growth factor
• 刊名：Molecular Immunology
• 出版年：2013
• 出版时间：November, 2013
• 年：2013
• 卷：56
• 期：1-2
• 页码：91-97
• 全文大小：767 K

文摘

Preeclampsia is a major obstetric problem defined by new-onset hypertension and proteinuria associated with compromised placental perfusion. Although activation of the complement system is increased in preeclampsia compared to normal pregnancy, it remains unclear whether excess complement activation is a cause or consequence of placental ischemia. Therefore, we hypothesized that complement activation is critical for placental ischemia-induced hypertension. We employed the reduced utero-placental perfusion pressure (RUPP) model of placental ischemia in the rat to induce hypertension in the third trimester and evaluated the effect of inhibiting complement activation with a soluble recombinant form of an endogenous complement regulator, human complement receptor 1 (sCR1; CDX-1135). On day 14 of a 21-day gestation, rats received either RUPP or Sham surgery and 15 mg/kg/day sCR1 or saline intravenously on days 14-18. Circulating complement component 3 decreased and complement activation product C3a increased in RUPP vs. Sham (p < 0.05), indicating complement activation had occurred. Mean arterial pressure (MAP) measured on day 19 increased in RUPP vs. Sham rats (109.8 ¡À 2.8 mmHg vs. 93.6 ¡À 1.6 mmHg). Treatment with sCR1 significantly reduced elevated MAP in RUPP rats (98.4 ¡À 3.6 mmHg, p < 0.05) and reduced C3a production. Vascular endothelial growth factor (VEGF) decreased in RUPP compared to Sham rats, and the decrease in VEGF was not affected by sCR1 treatment. Thus, these studies have identified a mechanistic link between complement activation and the pregnancy complication of hypertension apart from free plasma VEGF and have identified complement inhibition as a potential treatment strategy for placental ischemia-induced hypertension in preeclampsia.