The effect of immune factors, tumor necrosis factor-alpha, and agonistic autoantibodies to the angiotensin II type I receptor on soluble fms-like tyrosine-1 and soluble endoglin production in response to hypertension during pregnancy.
BACKGROUND
Preeclampsia is considered a disease of immunological origin associated with abnormalities in inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), and activated lymphocytes secreting autoantibodies to the angiotensin II receptor (AT1-AA). Recent studies have also demonstrated that an imbalance of angiogenic factors, soluble fms-like tyrosine kinase (sFlt-1), and sEndoglin, exists in preeclampsia; however, the mechanisms that initiate their overproduction are unclear.


METHODS
To determine the role of immune regulation of these factors, circulating and placental sFlt-1 and/or sEndoglin was examined from pregnant rats chronically treated with TNF-alpha or AT1-AA. On day 19 of gestation blood pressure was analyzed and serum and tissues were collected. Placental villous explants were excised and cultured on matrigel coated inserts for 24 h and sFlt-1 and sEndoglin was measured from media.


RESULTS
In response to TNF-alpha-induced hypertension, sFlt-1 increased from 180 +/- 5 to 2,907 +/- 412 pg/ml. sFlt-1 was also increased from cultured placental explants of TNF-alpha induced hypertensive pregnant rats (n = 12) (2,544 +/- 1,132 pg/ml) vs. explants from normal pregnant (NP) rats (n = 12) (2,189 +/- 586 pg/ml) where as sEng was undetectable. Circulating sFlt-1 increased from 245 +/- 38 to 3,920 +/- 798 pg/ml in response to AT1-AA induced hypertension. sFlt-1 levels were higher (3,400 +/- 350 vs. 2,480 +/- 900 pg/ml) in placental explants from AT1-AA infused rats (n = 12) than NP rats (n = 7). In addition, sEndoglin increased from 30 +/- 2.7 to 44 +/- 3.3 pg/ml (P < 0.047) in AT1-AA infused rats but was undetectable in the media of the placental explants.


CONCLUSIONS
These data suggest that immune factors may serve as an important stimulus for both sFlt-1 and sEndoglin production in response to placental ischemia.
Parrish
Marc R
MR
Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, USA.
Murphy
Sydney R
SR
Rutland
Sarah
S
Wallace
Kedra
K
Wenzel
Katrin
K
Wallukat
Gerd
G
Keiser
Sharon
S
Ray
Lillian Fournier
LF
Dechend
Ralf
R
Martin
James N
JN
Granger
Joey P
JP
LaMarca
Babbette
B
D000818:Animals; D001323:Autoantibodies / Q000502:physiology*; D000071063:Endoglin; D005260:Female; D006973:Hypertension / Q000097:blood*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood*
D001323:Autoantibodies; D000071063:Endoglin; C501740:Eng protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D044140:Receptor, Angiotensin, Type 1; D014409:Tumor Necrosis Factor-alpha; D040281:Vascular Endothelial Growth Factor Receptor-1