The role of phosphoglycerate dehydrogenase (PHGDH), a key enzyme of the serine synthesis pathway (SSP), in endothelial cells (ECs) remains poorly characterized. We report that mouse neonates with EC-specific PHGDH deficiency suffer lethal vascular defects within days of gene inactivation, due to reduced EC proliferation and survival. In addition to nucleotide synthesis impairment, PHGDH knockdown (PHGDH^KD) caused oxidative stress, due not only to decreased glutathione and NADPH synthesis but also to mitochondrial dysfunction. Electron transport chain (ETC) enzyme activities were compromised upon PHGDH^KD because of insufficient heme production due to cellular serine depletion, not observed in other cell types. As a result of heme depletion, elevated reactive oxygen species levels caused EC demise. Supplementation of hemin in PHGDH^KD ECs restored ETC function and rescued the apoptosis and angiogenesis defects. These data argue that ECs die upon PHGDH inhibition, even without external serine deprivation, illustrating an unusual importance of serine synthesis for ECs.

中文翻译：

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通过PHGDH合成丝氨酸对于内皮细胞中血红素的产生至关重要。

磷酸甘油酸脱氢酶（PHGDH）是丝氨酸合成途径（SSP）的关键酶，在内皮细胞（ECs）中的作用仍然不清楚。我们报告说，由于EC增殖和存活率降低，具有EC特异性PHGDH缺乏症的小鼠新生儿在基因失活的几天内会遭受致命的血管缺陷。除核苷酸合成受损外，PHGDH敲除（PHGDH ^KD）还会引起氧化应激，这不仅是由于谷胱甘肽和NADPH合成减少，而且是由于线粒体功能障碍。PHGDH ^KD损害了电子传输链（ETC）的酶活性由于细胞丝氨酸耗竭导致血红素生成不足，在其他类型的细胞中未观察到。血红素耗竭的结果是，活性氧水平升高导致EC死亡。在PHGDH ^KD EC中补充血红素可恢复ETC功能并挽救细胞凋亡和血管生成缺陷。这些数据表明，即使没有外部丝氨酸剥夺，EC也会因PHGDH抑制而死亡，这说明丝氨酸合成对EC的异常重要性。