Recent in vitro studies have reported that
heme oxygenase 1 (HO-1) downregulates the angiostatic
protein soluble
fms-like tyrosine kinase 1 from placental villous explants and that the HO-1 metabolites CO and
bilirubin negatively regulate
endothelin 1 and
reactive oxygen species. Although soluble
fms-like tyrosine kinase 1,
endothelin 1, and
reactive oxygen species have been implicated in the pathophysiology of
hypertension during
preeclampsia and in response to placental
ischemia in pregnant rats, it is unknown whether chronic induction of HO-1 alters the hypertensive response to placental
ischemia. The present study examined the hypothesis that HO-1 induction in a rat model of placental
ischemia would beneficially affect blood pressure, angiogenic balance,
superoxide, and
endothelin 1 production in the ischemic placenta. To achieve this goal we examined the effects of
cobalt protoporphyrin, an HO-1 inducer, in the reduced uterine perfusion pressure (RUPP) placental
ischemia model and in normal pregnant rats. In response to RUPP treatment, mean arterial pressure increases 29 mm Hg (136±7 versus 106±5 mm Hg), which is significantly attenuated by
cobalt protoporphyrin (118±5 mm Hg). Although RUPP treatment causes placental soluble
fms-like tyrosine kinase 1/
vascular endothelial growth factor ratios to alter significantly to an angiostatic balance (1.00±0.10 versus 1.27±0.20), treatment with
cobalt protoporphyrin causes a significant shift in the ratio to an angiogenic balance (0.68±0.10). Placental
superoxide increased in RUPP (952.5±278.8 versus 243.9±70.5 relative light units/min per milligram) but was significantly attenuated by HO-1 induction (482.7±117.4 relative light units/min per milligram). Also, the
preproendothelin message was significantly increased in RUPP, which was prevented by
cobalt protoporphyrin. These data indicate that HO-1, or its metabolites, is a potential therapeutic for the treatment of
preeclampsia.