Ahmed A, Rahman M, Zhang X, Acevedo C H, Nijjar S, Rushton I, Bussolati B, St John J
Department of Reproductive and Vascular Biology, The University of Birmingham, Birmingham Women's Hospital, Edgbaston, UK.
Mol Med. 2000 May;6(5):391-409.
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.
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 (TNFalpha) induced placental damage and on feto-placental circulation was studied.
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 TNFalpha-mediated cellular damage in placental villous explants, as assessed by lactate dehydrogenase leakage (p < 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. Hemin-induced vessel relaxation and CO production was inhibited by HO inhibitor, tin protoporphyrin IX.
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.
妊娠的特征为类似炎症的过程，而子痫前期可能会加剧这种情况。血红素加氧酶（HO）可生成诱导血管舒张的一氧化碳（CO）以及作为内源性抗氧化剂的胆绿素。
我们使用逆转录聚合酶链反应（RT-PCR）、核糖核酸酶保护分析、免疫印迹和免疫组织化学方法，检测了HO-1和HO-2在正常及子痫前期胎盘组织中的表达及定位。此外，还研究了HO激活对肿瘤坏死因子-α（TNFα）诱导的胎盘损伤以及对胎儿-胎盘循环的影响。
我们首次证明了HO作为一种内源性胎盘因子，参与细胞保护和胎盘血管舒张。与孕早期胎盘相比，足月时HO-1水平显著升高，表明其在胎盘血管发育和调节中的作用。HO-1主要定位于血管外结缔组织，该组织在发育中的血管周围形成血管周围收缩鞘。HO-2定位于毛细血管以及绒毛间质，滋养层染色较弱。通过乳酸脱氢酶泄漏评估，HO-1的诱导导致胎盘绒毛外植体中TNFα介导的细胞损伤显著减轻（p < 0.01）。与孕周匹配的正常妊娠相比，子痫前期妊娠胎盘组织中HO-1蛋白显著减少。这表明HO-1激活受损可能会损害代偿机制，使胎盘易受细胞损伤并随后导致母体内皮细胞激活。等长收缩性研究表明，氯高铁血红素使U46619预收缩的胎盘动脉血管张力降低61%。HO抑制剂锡原卟啉IX可抑制氯高铁血红素诱导的血管舒张和CO生成。
我们的研究结果确立了HO-1作为一种内源性系统，可保护胎盘免受细胞毒性损伤，确定了HO-CO途径对胎儿-胎盘循环的调节作用，并为研究子痫前期疾病提供了新方法。
