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1.
PLoS One ; 10(7): e0132063, 2015.
Article in English | MEDLINE | ID: mdl-26135305

ABSTRACT

Preeclampsia is characterized by reduced placental perfusion with placental ischemia and hypertension during pregnancy. Preeclamptic women also exhibit a heightened inflammatory state and greater number of neutrophils in the vasculature compared to normal pregnancy. Since neutrophils are associated with tissue injury and inflammation, we hypothesized that neutrophils are critical to placental ischemia-induced hypertension and fetal demise. Using the reduced uteroplacental perfusion pressure (RUPP) model of placental ischemia-induced hypertension in the rat, we determined the effect of neutrophil depletion on blood pressure and fetal resorptions. Neutrophils were depleted with repeated injections of polyclonal rabbit anti-rat polymorphonuclear leukocyte (PMN) antibody (antiPMN). Rats received either antiPMN or normal rabbit serum (Control) on 13.5, 15.5, 17.5, and 18.5 days post conception (dpc). On 14.5 dpc, rats underwent either Sham surgery or clip placement on ovarian arteries and abdominal aorta to reduce uterine perfusion pressure (RUPP). On 18.5 dpc, carotid arterial catheters were placed and mean arterial pressure (MAP) was measured on 19.5 dpc. Neutrophil-depleted rats had reduced circulating neutrophils from 14.5 to 19.5 dpc compared to Control, as well as decreased neutrophils in lung and placenta on 19.5 dpc. MAP increased in RUPP Control vs Sham Control rats, and neutrophil depletion attenuated this increase in MAP in RUPP rats without any effect on Sham rats. The RUPP-induced increase in fetal resorptions and complement activation product C3a were not affected by neutrophil depletion. Thus, these data are the first to indicate that neutrophils play an important role in RUPP hypertension and that cells of the innate immune system may significantly contribute to pregnancy-induced hypertension.


Subject(s)
Hypertension, Pregnancy-Induced/prevention & control , Ischemia/physiopathology , Leukocyte Reduction Procedures , Neutrophils/physiology , Placenta/blood supply , Animals , Complement C3a/analysis , Disease Models, Animal , Female , Hypertension, Pregnancy-Induced/blood , Hypertension, Pregnancy-Induced/etiology , Hypertension, Pregnancy-Induced/immunology , Hypertension, Pregnancy-Induced/physiopathology , Immune Sera , Immunity, Innate , Ischemia/complications , Ischemia/immunology , Leukocyte Count , Neutrophils/immunology , Oxidative Stress , Placental Circulation , Pre-Eclampsia/etiology , Pre-Eclampsia/immunology , Pre-Eclampsia/physiopathology , Pre-Eclampsia/prevention & control , Pregnancy , Rats , Rats, Sprague-Dawley , Vascular Endothelial Growth Factor A/blood
2.
J Pharmacol Exp Ther ; 351(2): 344-51, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25150279

ABSTRACT

Early-onset pre-eclampsia is characterized by decreased placental perfusion, new-onset hypertension, angiogenic imbalance, and endothelial dysfunction associated with excessive activation of the innate immune complement system. Although our previous studies demonstrated that inhibition of complement activation attenuates placental ischemia-induced hypertension using the rat reduced uterine perfusion pressure (RUPP) model, the important product(s) of complement activation has yet to be identified. We hypothesized that antagonism of receptors for complement activation products C3a and C5a would improve vascular function and attenuate RUPP hypertension. On gestational day (GD) 14, rats underwent sham surgery or vascular clip placement on ovarian arteries and abdominal aorta (RUPP). Rats were treated once daily with the C5a receptor antagonist (C5aRA), PMX51 (acetyl-F-[Orn-P-(D-Cha)-WR]), the C3a receptor antagonist (C3aRA), SB290157 (N(2)-[(2,2-diphenylethoxy)acetyl]-l-arginine), or vehicle from GD 14-18. Both the C3aRA and C5aRA attenuated placental ischemia-induced hypertension without affecting the decreased fetal weight or decreased concentration of free circulating vascular endothelial growth factor (VEGF) also present in this model. The C5aRA, but not the C3aRA, attenuated placental ischemia-induced increase in heart rate and impaired endothelial-dependent relaxation. The C3aRA abrogated the acute pressor response to C3a peptide injection, but it also unexpectedly attenuated the placental ischemia-induced increase in C3a, suggesting nonreceptor-mediated effects. Overall, these results indicate that both C3a and C5a are important products of complement activation that mediate the hypertension regardless of the reduction in free plasma VEGF. The mechanism by which C3a contributes to placental ischemia-induced hypertension appears to be distinct from that of C5a, and management of pregnancy-induced hypertension is likely to require a broad anti-inflammatory approach.


Subject(s)
Cardiovascular System/immunology , Cardiovascular System/physiopathology , Complement Activation/immunology , Complement C3a/immunology , Complement C5a/immunology , Hypertension/immunology , Hypertension/physiopathology , Animals , Complement C3a/antagonists & inhibitors , Complement C5a/antagonists & inhibitors , Disease Models, Animal , Endothelium, Vascular/immunology , Endothelium, Vascular/physiopathology , Female , Heart Rate/immunology , Ischemia/immunology , Ischemia/physiopathology , Placenta/immunology , Pregnancy , Rats , Receptors, Complement/immunology , Vascular Endothelial Growth Factor A/immunology
3.
Mol Immunol ; 56(1-2): 91-7, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23685261

ABSTRACT

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.


Subject(s)
Complement Activation/physiology , Hypertension/physiopathology , Ischemia/physiopathology , Placenta/physiopathology , Animals , Arterial Pressure/drug effects , Carotid Arteries/drug effects , Carotid Arteries/physiopathology , Complement Activation/drug effects , Complement C3/metabolism , Dose-Response Relationship, Drug , Female , Humans , Hypertension/blood , Hypertension/metabolism , In Vitro Techniques , Male , Nitroprusside/pharmacology , Placenta/blood supply , Placenta/metabolism , Pre-Eclampsia/blood , Pre-Eclampsia/metabolism , Pre-Eclampsia/physiopathology , Pregnancy , Rats , Rats, Sprague-Dawley , Receptors, Complement/administration & dosage , Time Factors , Uterus/blood supply , Uterus/metabolism , Uterus/physiopathology , Vascular Endothelial Growth Factor A/blood , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-1/blood , Vascular Endothelial Growth Factor Receptor-1/metabolism , Vasodilation/drug effects , Vasodilator Agents/pharmacology
4.
Gen Comp Endocrinol ; 171(3): 319-25, 2011 May 01.
Article in English | MEDLINE | ID: mdl-21354158

ABSTRACT

Thyroid-stimulating hormone (TSH) is an important regulator of the hypothalamic-pituitary-thyroid (HPT) axis in Xenopus laevis. To evaluate the role of this hormone on developing tadpoles, immunologically-based Western blots and sandwich ELISAs were developed for measuring intracellular (within pituitaries), secreted (ex vivo pituitary culture), and circulating (serum) amounts. Despite the small size of the tadpoles, these methods were able to easily measure intracellular and secreted TSH, and circulating TSH was measurable in situations where high levels were induced. The method was validated after obtaining a highly purified and enriched TSH sample using anti-TSH-ß antibodies conjugated to magnetic beads. Subsequent mass-spectrometric analysis of the bands from SDS-PAGE and Western procedures identified the presence of amino acid sequences corresponding to TSH subunits. The purified sample was also used to prepare standard curves for quantitative analysis. The Western and ELISA methods had limits of detection in the low nanogram range. While the majority of the developmental work for these methods was done with X. laevis, the methods also detected TSH in Xenopus tropicalis. To our knowledge this is the first report of a specific detection method for TSH in these species, and the first to measure circulating TSH in amphibians. Examples of the utility of the methods include measuring a gradual increase in pituitary TSH at key stages of development, peaking at stages 58-62; the suppression of TSH secretion from cultured pituitaries in the presence of thyroid hormone (T4); and increases in serum TSH following thyroidectomy.


Subject(s)
Thyrotropin/metabolism , Xenopus laevis/metabolism , Xenopus/metabolism , Animals , Blotting, Western , Electrophoresis, Polyacrylamide Gel , Enzyme-Linked Immunosorbent Assay , Pituitary Gland/metabolism , Thyrotropin/blood , Xenopus/blood , Xenopus laevis/blood
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