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.

Abstract

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.

• Authors: Marc R Parrish, Sydney R Murphy, Sarah Rutland, Kedra Wallace, Katrin Wenzel, Gerd Wallukat, Sharon Keiser, Lillian Fournier Ray, Ralf Dechend, James N Martin, Joey P Granger, Babbette LaMarca
• Journal: American journal of hypertension (Am J Hypertens) Vol. 23 Issue 8 Pg. 911-6 (Aug 2010) ISSN: 1941-7225 [Electronic] United States
• PMID: 20431529 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantibodies
• Endoglin
• Eng protein, rat
• Intracellular Signaling Peptides and Proteins
• Receptor, Angiotensin, Type 1
• Tumor Necrosis Factor-alpha
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Animals
• Autoantibodies (physiology)
• Endoglin
• Female
• Hypertension (blood)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Pregnancy
• Pregnancy Complications, Cardiovascular (immunology)
• Rats
• Rats, Sprague-Dawley
• Receptor, Angiotensin, Type 1 (immunology)
• Tumor Necrosis Factor-alpha (adverse effects)
• Vascular Endothelial Growth Factor Receptor-1 (blood)