Induction of Placental Heme Oxygenase-1 Is Protective Against TNFα-induced Cytotoxicity and Promotes Vessel Relaxation

Abstract

Background: Pregnancy is characterized by an inflammatory-like process and this may be exacerbated in preeclampsia. The heme oxygenase (HO) enzymes generate carbon monoxide (CO) that induces blood vessel relaxation and biliverdin 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 polymerase chain reaction (RT-PCR), RNase protection assay, immunoblotting and immunohistochemistry. In addition, the effect of HO activation on tumor necrosis factor-alpha (TNF␣) induced placental damage and on feto-placental 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 relaxation. HO-1 was significantly higher at term, compared with first trimester placentae indicating its role in placental vascular development and regulation. HO-1 predominantly localized in the extravascular connective tissue that forms the perivascular contractile sheath around the developing blood vessels. HO-2 was localized in the capillaries, as well as the villous stroma, with weak staining of trophoblast. Induction of HO-1 caused a significant attenuation of TNF␣mediated cellular damage in placental villous explants, as assessed by lactate dehydrogenase leakage (p Ͻ 0.01). HO-1 protein was significantly reduced in placentae from pregnancies complicated with preeclampsia, compared with gestationally matched normal pregnancies. This suggests that the impairment of HO-1 activation may compromise the compensatory mechanism and predispose the placenta to cellular injury and subsequent maternal endothelial cell activation. Isometric contractility studies showed that hemin reduced vascular tension by 61% in U46619-preconstricted placental arteries. Hemininduced vessel relaxation and CO production was inhibited by HO inhibitor, tin protoporphyrin IX. Conclusions: Our findings establish HO-1 as an endogenous system that offers 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.

Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation

“…In human pregnancies, HMOX-1 is expressed in the placenta and decidua (29,(64)(65)(66)(67)(68)(69). Placental HMOX-1 expression has been described as being significantly higher in term human placentas (66), when levels of progesterone as well as estradiol are significantly higher than in the first trimester.…”

“…Placental HMOX-1 expression has been described as being significantly higher in term human placentas (66), when levels of progesterone as well as estradiol are significantly higher than in the first trimester. This supports the notion that HMOX-1 is modulated by progesterone during human pregnancies (64)(65)(66).…”

“…Placental HMOX-1 expression has been described as being significantly higher in term human placentas (66), when levels of progesterone as well as estradiol are significantly higher than in the first trimester. This supports the notion that HMOX-1 is modulated by progesterone during human pregnancies (64)(65)(66). The functional role of placental HMOX-1 in promoting vascularization during normally progressing pregnancies, or its potential modulation in pregnancy pathologies such as IUGR, remains unclear, probably due to the use of tissue from preterm versus full-term pregnancies, low sample numbers, tissue heterogeneity, or different detection methods.…”

Alteration of Serum Soluble Endoglin Levels after the Onset of Preeclampsia Is More Pronounced in Women with Early-Onset

“…Since several studies have supported the hypothesis that decreased biologically available NO is central to the pathogenesis of hypertension in women with preeclampsia (23), the inhibition of eNOS activation by intravascular sEng suggests a molecular basis for the elevated blood pressure (12). Most recently, one of the molecular mechanisms of the increases of both sFlt1 and sEng in preeclamptic women was elucidated by Cudmore et al (24); that is, heme oxygenase-1 (HO-1) is involved in negative regulation of both sFlt1 and sEng release, and it has already been reported that protein levels of HO-1 in preeclamptic placenta are decreased (25). The concentrations of sFlt1 and sEng in women with preeclampsia were positively correlated in our data and in previous reports (12,15,17), supporting the experimental results of Cudmore et al (24).…”

Blood glutathione redox status in gestational hypertension

“…In a recent study on human placentas, an induction of HOX-1 was protective against cytotoxic damage and promoted the vessel relaxation [37]. Furthermore, HOX-1 protein was significantly reduced in placentas from pregnancies complicated with pre-eclampsia, as compared with gestationally matched normal pregnancies [37].…”