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±2.8 mmHg vs 93.6±1.6 mmHg). Treatment with sCR1 significantly reduced elevated MAP in RUPP rats (98.4±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.

Background Infants born prematurely are often treated with supplemental oxygen, which can increase their risk for airway hyperresponsiveness (AHR), asthma, reduced lung function, and altered responses to respiratory viral infections later in childhood. Likewise, exposure of newborn mice to hyperoxia alters baseline pulmonary mechanics and the host response to influenza A virus infection in adult mice. Here, we use this mouse model to test the hypothesis that neonatal hyperoxia also promotes AHR and exacerbated allergen-induced symptoms in adult mice. Methods Baseline lung mechanics and AHR measured by methacholine provocation were assessed in adult male and female mice exposed to room air or 100% oxygen (hyperoxia) between postnatal days 0 – 4. AHR and lung inflammation were evaluated after adult female mice were sensitized with ovalbumin (OVA) plus alum and challenged with aerosolized OVA. Results: Baseline lung compliance increased and resistance decreased in adult female, but not male, mice exposed to neonatal hyperoxia compared to siblings exposed to room air. Neonatal hyperoxia significantly enhanced methacholine-induced AHR in female mice, but did not affect allergen-induced AHR to methacholine or lung inflammation. Conclusion Increased incidence of AHR and asthma is reported in children born prematurely and exposed to supplemental oxygen. Our findings in adult female mice exposed to hyperoxia as neonates suggest that this AHR reported in children born prematurely may reflect non-atopic wheezing due to intrinsic structural changes in airway development.

Preeclampsia is characterized by compromised placental perfusion and hypertension during pregnancy. Preeclamptic women exhibit a greater number of neutrophils (PMN) in the vasculature and a decrease in plasma free vascular endothelial growth factor (VEGF) compared to normal pregnancy.HypothesisPMN are critical to placental ischemia‐induced hypertension and decreased VEGF. Using the reduced uterine perfusion pressure (RUPP) model of placental ischemia‐induced hypertension, we determined the effect of PMN depletion on blood pressure and plasma VEGF. PMN were depleted with repeated injections of polyclonal rabbit anti‐rat neutrophil antibody (αPMN). On gestation day 14, clips were placed on the abdominal aorta and uterine arteries to decrease placental perfusion. RUPP and Sham rats received either αPMN or normal rabbit serum (Ctl) on gestation days 13, 14, 16, and 18, and mean arterial pressure (MAP) was measured via arterial catheter on day 19. PMN‐depleted rats had reduced circulating PMN (p<0.05) on day 14 compared to Ctl. MAP increased (p<0.05) in RUPP Ctl vs Sham Ctl rats, and PMN depletion attenuated this increase in MAP in RUPP rats (p=0.04) without any effect on Sham rats. The RUPP‐induced decrease in VEGF was not affected by PMN depletion. Thus, neutrophils are important in placental ischemia‐induced hypertension independent of plasma free VEGF concentrations. Support: NIH R15 HL109843.

Preeclampsia is characterized by compromised placental perfusion and new onset hypertension during pregnancy. The complement system is part of the innate immune system and complement activation is known to increase in preeclampsia.HypothesisComplement activation is critical for placental ischemia‐induced hypertension. To test the hypothesis, we used the reduced uteroplacental perfusion pressure (RUPP) model of placental ischemia to induce hypertension and determined the effect of inhibiting complement activation using a recombinant soluble form of an endogenous complement regulator, soluble complement receptor‐1 (sCR1; CDX‐1135). On gestation day 14 (term = 21 d) rats underwent sham surgery or clips were placed on the inferior abdominal aorta and ovarian arteries to create RUPP. RUPP and Sham animals received 15 mg/kg sCR1 or saline (Veh) on days 14–18 and mean arterial pressure (MAP) was measured day 19 via arterial catheter. Circulating complement component 3 decreased in RUPP vs Sham (p<0.05) suggesting the component had been cleaved and complement activation had occurred. MAP increased in RUPP‐Veh rats compared to Sham‐Veh rats (109 ± 3 vs 95 ± 3 mmHg), and sCR1 treatment significantly attenuated the increase in MAP in RUPP rats (99 ± 3 mmHg, p<0.05). Thus, inhibition of complement activation may be a viable treatment for hypertension in preeclampsia. Support: Univ Minn Grant‐in‐Aid & NIH HL109843.