A Critical Role of Interleukin-10 in Modulating Hypoxia-Induced Preeclampsia-Like Disease in Mice
Hypoxia has been implicated in the pathogenesis of preeclampsia, a hypertensive disorder of pregnancy. However, in vivo evidence and mechanistic understanding remain elusive. Preeclampsia is associated with impaired placental angiogenesis. We have recently shown that interleukin (IL)-10 can support trophoblast-driven endovascular crosstalk. Accordingly, we hypothesize that pathological levels of oxygen coupled with IL-10 deficiency induce severe preeclampsia-like features coupled with elevated production of antiangiogenic factors, apoptotic pathways, and placental injury. Exposure of pregnant wild-type and IL-10−/− mice to 9.5% oxygen resulted in graded placental injury and systemic symptoms of renal pathology, proteinuria (wild-type 645.15±115.73 versus 198.09±93.45; IL-10−/− 819.31±127.85 versus 221.45±82.73 μ g/mg/24 hours) and hypertension (wild-type 118.37±14.45 versus 78.67±14.07; IL-10−/− 136.03±22.59 versus 83.97±18.25 mm Hg). Recombinant IL-10 reversed hypoxia-induced features in pregnant IL-10−/− mice confirming the protective role of IL-10 in preeclampsia. Hypoxic exposure caused marked elevation of soluble fms-like tyrosine kinase 1 (110.8±20.1 versus 44.7±11.9 ng/mL) in IL-10−/− mice compared with their wild-type counterparts (81.6±13.1 versus 41.2±8.9 ng/mL), whereas soluble endoglin was induced to similar levels in both strains (approximately 380±50 versus 180±31 ng/mL). Hypoxia-induced elevation of p53 was associated with marked induction of proapoptotic protein Bax, downregulation of Bcl-2, and trophoblast-specific apoptosis in utero-placental tissue. Collectively, we conclude that severe preeclampsia pathology could be triggered under certain threshold oxygen levels coupled with intrinsic IL-10 deficiency, which lead to excessive activation of antiangiogenic and apoptotic pathways.
- Received September 22, 2010.
- Revision received October 10, 2010.
- Accepted December 22, 2010.
- © 2011 American Heart Association, Inc.