Induction of placental heme oxygenase-1 is protective against TNF alpha-induced cytotoxicity and promotes vessel relaxation

Background: Pregnancy is characterized by an inflammatory-like process and this may be exacerbated in preeclampsia. The heme oxygenase (HO) enzymes ge nerate carbon monoxide (CO) that induces blood vessel relaxation and bilive rdin that acts as an endogenous antioxidant. Materials and Methods: We examined the expression and localization of HO-1 and HO-2 in normal and preeclamptic placenta using reverse transcription po lymerase chain reaction (RT-PCR), RNase protection assay, immunoblotting an d immunohistochemistry. In addition, the effect of HO activation on tumor n ecrosis factor-alpha (TNF alpha) induced placental damage and on feto-place ntal circulation was studied. Results: We provide the first evidence for the role of HO as an endogenous placental factor involved with cytoprotection and placental blood vessel re laxation. HO-1 was significantly higher at term, compared with first trimes ter placentae indicating its role in placental vascular development and reg ulation. HO-1 predominantly localized in the extravascular connective tissu e that forms the perivascular contractile sheath around the developing bloo d vessels. HO-2 was localized in the capillaries, as well as the villous st roma, with weak staining of trophoblast. Induction of HO-1 caused a signifi cant attenuation of TNF alpha-mediated cellular damage in placental villous explants, as assessed by lactate dehydrogenase leakage (p < 0.01). HO-1 pr otein was significantly reduced in placentae from pregnancies complicated w ith preeclampsia, compared with gestationally matched normal pregnancies. T his suggests that the impairment of HO-1 activation may compromise the comp ensatory mechanism and predispose the placenta to cellular injury and subse quent maternal endothelial cell activation. Isometric contractility studies showed that hemin reduced vascular tension by 61% in U46619-preconstricted placental arteries. Hemin-induced vessel relaxation and CO production was inhibited by HO inhibitor, tin protoporphyrin IX. Conclusions: Our findings establish HO-1 as an endogenous system that offer s protection against cytotoxic damage in the placenta, identifies the HO-CO pathway to regulate feto-placental circulation and provides a new approach to study the disease of preeclampsia.