Heme oxygenase inhibition increases blood pressure in pregnant rats.

Maintenance of blood pressure and vascular function during pregnancy is dependent on a carefully orchestrated program of placental development that adequately supplies the developing uteroplacental unit with blood.1 Failure to adequately remodel the uterine vasculature can lead to chronic placental ischemia, now recognized as a central causative agent in several pregnancy pathologies, most notably preeclampsia.2 In recent years, research from numerous labs has identified a number of pathogenic agents produced by the placenta in response to placental ischemia—the VEGF antagonist soluble fms-like tyrosine kinase-1 (sFlt-1) and oxidative stress being major activated targets.3–7 However, even under nonpathological conditions, the placenta is a remarkably hypoxic organ, and it is not entirely clear what intrinsic pathways are responsible for keeping these potentially pathogenic agents in check. There is emerging evidence, however, that these 2 factors can be negatively regulated by the heme oxygenase (HO) system.8,9 HO is commonly considered a housekeeping protein responsible for the degradation of heme released from the breakdown of heme-containing proteins. Heme, a powerful pro-oxidant, is converted by HO into biliverdin, releasing the bioactive molecule carbon monoxide (CO) in the process. Biliverdin is then rapidly converted to bilirubin by biliverdin reductase, and both biliverdin and bililrubin have been shown to have potent antioxidant properties.10,11 HO, and particularly the inducible isoform HO-1, has recently become a target of interest in several pathological states, perhaps most notably hypertension. HO-1 or its metabolites have demonstrated beneficial effects in the treatment of many forms of experimental hypertension, including AngII-dependent, pulmonary, and renovascular hypertension.12–14 Manipulation of the HO-1 system as a therapeutic remains an active area of research. sFlt-1 is perhaps the best-characterized factor released by the ischemic placenta and is a soluble form of the VEGF receptor Flt-1. In the soluble form, sFlt-1 binds free VEGF and makes it unavailable for normal signaling, thereby acting as a potent VEGF antagonist.15 Interestingly, sFlt-1 is also produced at significantly elevated levels by the placenta during even healthy pregnancies, but this is balanced out by a concomitant increase in the VEGF family member placental growth factor (PlGF).16 Preeclampsia then is the imbalanced increase in sFlt-1 in proportion to VEGF/PlGF, but what keeps these factors in balance during normal gestation remains obscure. Intriguingly, several recent reports have demonstrated that HO-1, CO, and bilirubin could negatively affect sFlt-1 production in response to various stimuli.8,9 Oxidative stress has also been intensively studied as a cause of hypertension in response to placental ischemia. Preeclamptic placentas exhibit significant elevations in oxidative stress, and in experimental placental ischemia–induced and sFlt-1–induced hypertension, inhibition of reactive oxygen leads to significant attenuation of the associated hypertension.3,17 Given the hypoxic nature of the healthy placenta, it is not clear how the organ keeps oxidative stress under control. Several recent reports have demonstrated that HO-1 is important for placental development. Crossing of heterozygous HO-1+/- animals leads to significant defects in placental vascular development and structure and placental morphology. This is associated with prevalent fetal demise of the homozygous offspring, lowered fetal weight, decreased litter size, and altered vascular structure and placental morphology regardless of fetal genotype.18,19 However the effects of HO-1 disruption on blood pressure regulation, angiogenic balance, and oxidative stress in late gestation have not been examined. In this study, we have investigated the effect of pharmacological HO inhibition on blood pressure, angiogenic balance, and oxidative stress in late gestation. We demonstrate that HO inhibition leads to an antiangiogenic shift in the placenta, increased placental oxidative stress, and subsequently increased maternal blood pressure.