Hypoxia-inducible factor 1α (HIF1α) is a master regulator of biological processes in hypoxia. Yet, the mechanisms and biological consequences of aerobic HIF1α activation by intrinsic factors, particularly in normal (primary) cells, remain elusive. Here we show that HIF1α signalling is activated in several human primary vascular cells in normoxia and in vascular smooth muscle cells of normal human lungs. Mechanistically, aerobic HIF1α activation is mediated by paracrine secretion of three branched-chain α-ketoacids (BCKAs), which suppress PHD2 activity via direct inhibition and via LDHA-mediated generation of L-2-hydroxyglutarate. BCKA-mediated HIF1α signalling activation stimulated glycolytic activity and governed a phenotypic switch of pulmonary artery smooth muscle cells, which correlated with BCKA metabolic dysregulation and pathophenotypic changes in pulmonary arterial hypertension patients and male rat models. We thus identify BCKAs as previously unrecognized signalling metabolites that aerobically activate HIF1α and that the BCKA–HIF1α pathway modulates vascular smooth muscle cell function, an effect that may be relevant to pulmonary vascular pathobiology.

缺氧诱导因子 1α （HIF1α） 是缺氧中生物过程的主要调节因子。然而，内因子（特别是在正常（原代）细胞中激活需氧 HIF1α 的机制和生物学后果仍然难以捉摸。在这里，我们表明 HIF1α 信号在常氧的几种人类原代血管细胞和正常人肺的血管平滑肌细胞中被激活。从机制上讲，需氧 HIF1α 激活是由三种支链 α-酮酸 （BCKA） 的旁分泌介导的，这些支链通过直接抑制和 LDHA 介导的 L-2-羟基戊二酸的产生来抑制 PHD2 活性。BCKA 介导的 HIF1α 信号激活刺激糖酵解活性并控制肺动脉平滑肌细胞的表型转换，这与肺动脉高压患者和雄性大鼠模型的 BCKA 代谢失调和病理表型变化相关。因此，我们将 BCKA 确定为以前未被识别的信号代谢物，它们有氧激活 HIF1α，并且 BCKA-HIF1α 通路调节血管平滑肌细胞功能，这种作用可能与肺血管病理学有关。