Endothelial Cell Tetrahydrobiopterin Modulates Sensitivity to Ang (Angiotensin) II-Induced Vascular Remodeling, Blood Pressure, and Abdominal Aortic Aneurysm.
Endothelial Cell Tetrahydrobiopterin Modulates Sensitivity to Ang (Angiotensin) II-Induced Vascular Remodeling, Blood Pressure, and Abdominal Aortic Aneurysm.
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DOI：
10.1161/hypertensionaha.118.11144
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Douglas G
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文献类型：
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作者：
Chuaiphichai S;Rashbrook VS;Hale AB;Trelfa L;Patel J;McNeill E;Lygate CA;Channon KM;Douglas G
补充数字内容可在文本中找到。GTPCH（GTP环化水解酶1，由Gch 1编码）是合成四氢生物蝶呤所必需的;四氢生物蝶呤是内皮NO合酶功能的关键调节剂。我们先前已经表明，内皮细胞Gch 1选择性缺失的小鼠有轻度血管功能障碍，但血管疾病发病机制中内皮细胞四氢生物蝶呤缺乏的后果尚不清楚。我们研究了血管紧张素II（Ang）输注在内皮细胞Gch 1缺陷（Gch 1fl/flTie 2cre）小鼠的病理后果。Ang II（0.4 mg/kg/d，通过渗透压微泵给药）可显著降低Gch 1fl/flTie 2cre小鼠循环中四氢生物蝶呤水平，并显著增加主动脉中Nω-硝基-L-精氨酸甲酯可抑制的H2 O2生成。慢性治疗与此降压剂量的血管紧张素II导致血压显着增加，只有在Gch 1fl/flTie 2cre小鼠。这一发现反映了急性给药的血管紧张素II，其中增加的敏感性，血管紧张素II在升压和降压剂量。Gch 1fl/flTie 2ce小鼠慢性血管紧张素II输注导致阻力肠系膜动脉血管功能障碍，收缩反应增强，扩张反应降低，中膜肥大。在Gch 1fl/flTie 2ce小鼠的主动脉中也观察到血管重塑改变，腹主动脉瘤形成的发生率增加。这些研究结果表明，在调节血管紧张素II引起的血流动力学和结构变化，通过调节血压，阻力血管的结构变化，和动脉瘤形成的内皮细胞四氢生物蝶呤的具体要求。
Supplemental Digital Content is available in the text. GTPCH (GTP cyclohydrolase 1, encoded by Gch1) is required for the synthesis of tetrahydrobiopterin; a critical regulator of endothelial NO synthase function. We have previously shown that mice with selective loss of Gch1 in endothelial cells have mild vascular dysfunction, but the consequences of endothelial cell tetrahydrobiopterin deficiency in vascular disease pathogenesis are unknown. We investigated the pathological consequence of Ang (angiotensin) II infusion in endothelial cell Gch1 deficient (Gch1fl/flTie2cre) mice. Ang II (0.4 mg/kg per day, delivered by osmotic minipump) caused a significant decrease in circulating tetrahydrobiopterin levels in Gch1fl/flTie2cre mice and a significant increase in the Nω-nitro-L-arginine methyl ester inhabitable production of H2O2 in the aorta. Chronic treatment with this subpressor dose of Ang II resulted in a significant increase in blood pressure only in Gch1fl/flTie2cre mice. This finding was mirrored with acute administration of Ang II, where increased sensitivity to Ang II was observed at both pressor and subpressor doses. Chronic Ang II infusion in Gch1fl/flTie2ce mice resulted in vascular dysfunction in resistance mesenteric arteries with an enhanced constrictor and decreased dilator response and medial hypertrophy. Altered vascular remodeling was also observed in the aorta with an increase in the incidence of abdominal aortic aneurysm formation in Gch1fl/flTie2ce mice. These findings indicate a specific requirement for endothelial cell tetrahydrobiopterin in modulating the hemodynamic and structural changes induced by Ang II, through modulation of blood pressure, structural changes in resistance vessels, and aneurysm formation in the aorta.