PMID- 25150279
OWN - NLM
STAT- MEDLINE
DCOM- 20141117
LR  - 20211021
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 351
IP  - 2
DP  - 2014 Nov
TI  - Differential effects of complement activation products c3a and c5a on 
      cardiovascular function in hypertensive pregnant rats.
PG  - 344-51
LID - 10.1124/jpet.114.218123 [doi]
AB  - 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.
CI  - Copyright (c) 2014 by The American Society for Pharmacology and Experimental 
      Therapeutics.
FAU - Lillegard, Kathryn E
AU  - Lillegard KE
AD  - Department of Biomedical Sciences, University of Minnesota Medical School Duluth 
      (K.E.L., A.C.L.-J., J.W.O., J.M.P., A.J.B., B.J.E., J.S.G., J.F.R.) and 
      Department of Mathematics and Statistics, University of Minnesota Duluth 
      (R.R.R.), Duluth, Minnesota.
FAU - Loeks-Johnson, Alex C
AU  - Loeks-Johnson AC
AD  - Department of Biomedical Sciences, University of Minnesota Medical School Duluth 
      (K.E.L., A.C.L.-J., J.W.O., J.M.P., A.J.B., B.J.E., J.S.G., J.F.R.) and 
      Department of Mathematics and Statistics, University of Minnesota Duluth 
      (R.R.R.), Duluth, Minnesota.
FAU - Opacich, Jonathan W
AU  - Opacich JW
AD  - Department of Biomedical Sciences, University of Minnesota Medical School Duluth 
      (K.E.L., A.C.L.-J., J.W.O., J.M.P., A.J.B., B.J.E., J.S.G., J.F.R.) and 
      Department of Mathematics and Statistics, University of Minnesota Duluth 
      (R.R.R.), Duluth, Minnesota.
FAU - Peterson, Jenna M
AU  - Peterson JM
AD  - Department of Biomedical Sciences, University of Minnesota Medical School Duluth 
      (K.E.L., A.C.L.-J., J.W.O., J.M.P., A.J.B., B.J.E., J.S.G., J.F.R.) and 
      Department of Mathematics and Statistics, University of Minnesota Duluth 
      (R.R.R.), Duluth, Minnesota.
FAU - Bauer, Ashley J
AU  - Bauer AJ
AD  - Department of Biomedical Sciences, University of Minnesota Medical School Duluth 
      (K.E.L., A.C.L.-J., J.W.O., J.M.P., A.J.B., B.J.E., J.S.G., J.F.R.) and 
      Department of Mathematics and Statistics, University of Minnesota Duluth 
      (R.R.R.), Duluth, Minnesota.
FAU - Elmquist, Barbara J
AU  - Elmquist BJ
AD  - Department of Biomedical Sciences, University of Minnesota Medical School Duluth 
      (K.E.L., A.C.L.-J., J.W.O., J.M.P., A.J.B., B.J.E., J.S.G., J.F.R.) and 
      Department of Mathematics and Statistics, University of Minnesota Duluth 
      (R.R.R.), Duluth, Minnesota.
FAU - Regal, Ronald R
AU  - Regal RR
AD  - Department of Biomedical Sciences, University of Minnesota Medical School Duluth 
      (K.E.L., A.C.L.-J., J.W.O., J.M.P., A.J.B., B.J.E., J.S.G., J.F.R.) and 
      Department of Mathematics and Statistics, University of Minnesota Duluth 
      (R.R.R.), Duluth, Minnesota.
FAU - Gilbert, Jeffrey S
AU  - Gilbert JS
AD  - Department of Biomedical Sciences, University of Minnesota Medical School Duluth 
      (K.E.L., A.C.L.-J., J.W.O., J.M.P., A.J.B., B.J.E., J.S.G., J.F.R.) and 
      Department of Mathematics and Statistics, University of Minnesota Duluth 
      (R.R.R.), Duluth, Minnesota.
FAU - Regal, Jean F
AU  - Regal JF
AD  - Department of Biomedical Sciences, University of Minnesota Medical School Duluth 
      (K.E.L., A.C.L.-J., J.W.O., J.M.P., A.J.B., B.J.E., J.S.G., J.F.R.) and 
      Department of Mathematics and Statistics, University of Minnesota Duluth 
      (R.R.R.), Duluth, Minnesota jregal@d.umn.edu.
LA  - eng
GR  - R01 HL114096/HL/NHLBI NIH HHS/United States
GR  - R15 HL109843/HL/NHLBI NIH HHS/United States
GR  - R15-HL109843/HL/NHLBI NIH HHS/United States
GR  - R01-HL114096/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140822
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Receptors, Complement)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 80295-42-7 (Complement C3a)
RN  - 80295-54-1 (Complement C5a)
SB  - IM
MH  - Animals
MH  - Cardiovascular System/*immunology/*physiopathology
MH  - Complement Activation/*immunology
MH  - Complement C3a/antagonists & inhibitors/*immunology
MH  - Complement C5a/antagonists & inhibitors/*immunology
MH  - Disease Models, Animal
MH  - Endothelium, Vascular/immunology/physiopathology
MH  - Female
MH  - Heart Rate/immunology
MH  - Hypertension/*immunology/*physiopathology
MH  - Ischemia/immunology/physiopathology
MH  - Placenta/immunology
MH  - Pregnancy
MH  - Rats
MH  - Receptors, Complement/immunology
MH  - Vascular Endothelial Growth Factor A/immunology
PMC - PMC4201271
EDAT- 2014/08/26 06:00
MHDA- 2014/11/18 06:00
PMCR- 2015/11/01
CRDT- 2014/08/24 06:00
PHST- 2014/08/24 06:00 [entrez]
PHST- 2014/08/26 06:00 [pubmed]
PHST- 2014/11/18 06:00 [medline]
PHST- 2015/11/01 00:00 [pmc-release]
AID - jpet.114.218123 [pii]
AID - JPET_218123 [pii]
AID - 10.1124/jpet.114.218123 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2014 Nov;351(2):344-51. doi: 10.1124/jpet.114.218123. Epub 
      2014 Aug 22.