Department of Reproductive and Vascular Biology, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
Biochem Soc Trans. 2009 Dec;37(Pt 6):1237-42. doi: 10.1042/BST0371237.
Pre-eclampsia, a pregnancy-specific multi-organ syndrome characterized by widespread endothelial damage, is a new risk factor for cardiovascular disease. No therapies exist to prevent or treat this condition, even to achieve a modest improvement in pregnancy length or birth weight. Co-administration of soluble VEGFR-1 [VEGF (vascular endothelial growth factor) receptor-1; more commonly known as sFlt-1 (soluble Fms-like tyrosine kinase-1)] and sEng (soluble endoglin) to pregnant rats elicits severe pre-eclampsia-like symptoms. These two anti-angiogenic factors are increased dramatically prior to the clinical onset of pre-eclampsia and are quite possibly the 'final common pathway' responsible for the accompanying signs of hypertension and proteinuria as they can be reversed by VEGF administration in animal models. HO-1 (haem oxygenase-1), an anti-inflammatory enzyme, and its metabolite, CO (carbon monoxide), exert protective effects in several organs against oxidative stimuli. In a landmark publication, we showed that the HO-1 pathway inhibits sFlt-1 and sEng in cultured cells and human placental tissue explants. Both CO and NO (nitric oxide) promote vascular homoeostasis and vasodilatation, and activation of VEGFR-1 or VEGFR-2 induced eNOS (endothelial nitric oxide synthase) phosphorylation, NO release and HO-1 expression. Our studies established the HO-1/CO pathway as a negative regulator of cytokine-induced sFlt-1 and sEng release and eNOS as a positive regulator of VEGF-mediated vascular morphogenesis. These findings provide compelling evidence for a protective role of HO-1 in pregnancy and identify it as a target for the treatment of pre-eclampsia. Any agent that is known to up-regulate HO-1, such as statins, may have potential as a therapy. Any intervention achieving even a modest prolongation of pregnancy or amelioration of the condition could have a significant beneficial health impact worldwide.
子痫前期是一种妊娠特异性多器官综合征，其特征为广泛的内皮损伤，是心血管疾病的新危险因素。目前尚无预防或治疗这种疾病的方法，甚至无法适度延长妊娠时间或增加出生体重。将可溶性 VEGFR-1（血管内皮生长因子受体-1；通常称为 sFlt-1（可溶性 Fms 样酪氨酸激酶-1））和 sEng（可溶性内皮糖蛋白）共同给予妊娠大鼠可引发类似子痫前期的严重症状。这两种抗血管生成因子在子痫前期临床发作前显著增加，很可能是导致高血压和蛋白尿的“共同最终途径”，因为它们可以在动物模型中通过 VEGF 给药逆转。HO-1（血红素加氧酶-1）是一种抗炎酶，其代谢产物 CO（一氧化碳）在几个器官中对氧化刺激具有保护作用。在一项具有里程碑意义的研究中，我们表明 HO-1 途径可抑制培养细胞和人胎盘组织外植体中的 sFlt-1 和 sEng。CO 和 NO（一氧化氮）均可促进血管稳态和血管舒张，激活 VEGFR-1 或 VEGFR-2 可诱导 eNOS（内皮型一氧化氮合酶）磷酸化、NO 释放和 HO-1 表达。我们的研究确立了 HO-1/CO 途径作为细胞因子诱导的 sFlt-1 和 sEng 释放的负调节剂，以及 eNOS 作为 VEGF 介导的血管形态发生的正调节剂。这些发现为 HO-1 在妊娠中的保护作用提供了有力证据，并将其确定为治疗子痫前期的靶点。任何已知可上调 HO-1 的药物，如他汀类药物，都可能具有治疗潜力。任何能够适度延长妊娠时间或改善病情的干预措施都可能对全球健康产生重大有益影响。
