Cell-autonomous role of endothelial GTP cyclohydrolase 1 and tetrahydrobiopterin in blood pressure regulation.
Cell-autonomous role of endothelial GTP cyclohydrolase 1 and tetrahydrobiopterin in blood pressure regulation.
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DOI：
10.1161/hypertensionaha.114.03089
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发表时间：
2014-09
期刊：
影响因子：
--
通讯作者：
Channon KM
中科院分区：
文献类型：
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作者：
Chuaiphichai S;McNeill E;Douglas G;Crabtree MJ;Bendall JK;Hale AB;Alp NJ;Channon KM
四氢生物蝶呤 (BH4) 是内皮一氧化氮合酶 (eNOS) 功能和 NO 生成的重要辅助因子。 BH4 水平的升高可以防止 eNOS 解偶联，并可以改善血管疾病状态下的内皮功能障碍。然而，eNOS 功能中内皮细胞 BH4 生物合成的生理要求仍不清楚。我们构建了一种内皮细胞特异性删除 GCH1 的新型小鼠模型，该模型编码 GTP 环化水解酶 1（BH4 生物合成的必需酶），以测试体内内皮 BH4 生物合成的细胞自主需求。将具有 floxed GCH1 等位基因 (GCH1fl/fl) 的小鼠与 Tie2cre 小鼠杂交，以删除内皮细胞中的 GCH1。 GCH1fl/flTie2cre 小鼠表现出几乎不存在内皮NO 生物活性并且显着增加O2·- 产生。 GCH1fl/flTie2cre 主动脉和肠系膜动脉对去氧肾上腺素的血管收缩作用增强，对乙酰胆碱和 SLIGRL 的内皮依赖性血管舒张作用受损。 GCH1fl/flTie2cre 主动脉中的内皮依赖性血管舒张部分是由 eNOS 衍生的过氧化氢 (H2O2) 介导的，它通过可溶性鸟苷酸环化酶介导血管舒张。在主动脉环中体外补充 BH4 类似物 sepiapterin 可恢复正常内皮功能，并消除 GCH1fl/flTie2cre 主动脉中 eNOS 衍生的 H2O2 产生。 GCH1fl/flTie2cre 小鼠的全身血压高于野生型同窝小鼠，NOS 抑制剂 NG-硝基-L-精氨酸甲酯可使血压正常化。总而言之，这些研究揭示了内皮细胞在调节血管张力和血压方面对 GCH1 和 BH4 的自主需求，并确定内皮细胞 BH4 作为 NO 的关键调节剂，而 H2O2 作为替代的 eNOS 衍生的内皮衍生舒张因子。
Tetrahydrobiopterin (BH4) is an essential cofactor for endothelial nitric oxide synthase (eNOS) function and NO generation. Augmentation of BH4 levels can prevent eNOS uncoupling and can improve endothelial dysfunction in vascular disease states. However, the physiological requirement for de novo endothelial cell BH4 biosynthesis in eNOS function remains unclear. We generated a novel mouse model with endothelial cell–specific deletion of GCH1, encoding GTP cyclohydrolase 1, an essential enzyme for BH4 biosynthesis, to test the cell-autonomous requirement for endothelial BH4 biosynthesis in vivo. Mice with a floxed GCH1 allele (GCH1fl/fl) were crossed with Tie2cre mice to delete GCH1 in endothelial cells. GCH1fl/flTie2cre mice demonstrated virtually absent endothelial NO bioactivity and significantly greater O2·- production. GCH1fl/flTie2cre aortas and mesenteric arteries had enhanced vasoconstriction to phenylephrine and impaired endothelium-dependent vasodilatations to acetylcholine and SLIGRL. Endothelium-dependent vasodilatations in GCH1fl/flTie2cre aortas were, in part, mediated by eNOS-derived hydrogen peroxide (H2O2), which mediated vasodilatation through soluble guanylate cyclase. Ex vivo supplementation of aortic rings with the BH4 analogue sepiapterin restored normal endothelial function and abolished eNOS-derived H2O2 production in GCH1fl/flTie2cre aortas. GCH1fl/flTie2cre mice had higher systemic blood pressure than wild-type littermates, which was normalized by NOS inhibitor, NG-nitro-L-arginine methyl ester. Taken together, these studies reveal an endothelial cell-autonomous requirement for GCH1 and BH4 in regulation of vascular tone and blood pressure and identify endothelial cell BH4 as a pivotal regulator of NO versus H2O2 as alternative eNOS-derived endothelial-derived relaxing factors.