Department of Pathology, Anatomy and Cell Biology and the Cell Biology and Signaling Program, Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA.
Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA.
Matrix Biol. 2020 Aug;90:1-19. doi: 10.1016/j.matbio.2020.02.001. Epub 2020 Feb 19.
Hyaluronan plays a key role in regulating inflammation and tumor angiogenesis. Of the three transmembrane hyaluronan synthases, HAS2 is the main pro-angiogenic enzyme responsible for excessive hyaluronan production. We discovered that HAS2 was degraded in vascular endothelial cells via autophagy evoked by nutrient deprivation, mTOR inhibition, or pro-autophagic proteoglycan fragments endorepellin and endostatin. Using live-cell and super-resolution confocal microscopy, we found that protracted autophagy evoked a dynamic interaction between HAS2 and ATG9A, a key transmembrane autophagic protein. This regulatory axis of HAS2 degradation occurred in various cell types and species and in vivo upon nutrient deprivation. Inhibiting in vivo autophagic flux via chloroquine showed increased levels of HAS2 in the heart and aorta. Functionally, autophagic induction via endorepellin or mTOR inhibition markedly suppressed extracellular hyaluronan production in vascular endothelial cells and inhibited ex vivo angiogenic sprouting. Thus, we propose autophagy as a novel catabolic mechanism regulating hyaluronan production in endothelial cells and demonstrate a new link between autophagy and angiogenesis that could lead to potential therapeutic modalities for angiogenesis.
透明质酸在调节炎症和肿瘤血管生成中发挥着关键作用。在三种跨膜透明质酸合酶中，HAS2 是主要的促血管生成酶，负责过量透明质酸的产生。我们发现，营养剥夺、mTOR 抑制或促自噬蛋白聚糖片段内皮抑素和 endorepellin 可诱发血管内皮细胞中的自噬，从而使 HAS2 降解。通过活细胞和超分辨率共聚焦显微镜，我们发现，持续性自噬会引发 HAS2 与 ATG9A（一种关键的跨膜自噬蛋白）之间的动态相互作用。这种 HAS2 降解的调节轴在各种细胞类型和物种中以及营养剥夺时的体内均存在。通过氯喹抑制体内自噬流，会导致心脏和主动脉中 HAS2 水平升高。功能上，通过内皮抑素或 mTOR 抑制诱导自噬会显著抑制血管内皮细胞中细胞外透明质酸的产生，并抑制体外血管生成发芽。因此，我们提出自噬是一种调节内皮细胞透明质酸产生的新型分解代谢机制，并证明自噬与血管生成之间存在新的联系，这可能为血管生成提供潜在的治疗方法。
