Tumor Microenvironment and Cancer Immunology Program, Cancer Center, Cardiovascular Metabolism Program, Center for Metabolic Origins of Disease, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, 6400 Sanger Road, Orlando, FL, 32827, USA.
Nat Commun. 2017 Nov 23;8(1):1720. doi: 10.1038/s41467-017-01865-x.
The formation of endothelial lumen is fundamental to angiogenesis and essential to the oxygenation of hypoxic tissues. The molecular mechanism underlying this important process remains obscure. Here, we show that Akt activation by a Ras homolog, R-Ras, stabilizes the microtubule cytoskeleton in endothelial cells leading to endothelial lumenogenesis. The activation of Akt by the potent angiogenic factor VEGF-A does not strongly stabilize microtubules or sufficiently promote lumen formation, hence demonstrating a distinct role for the R-Ras-Akt axis. We show in mice that this pathway is important for the lumenization of new capillaries and microvessels developing in ischemic muscles to allow sufficient tissue reperfusion after ischemic injury. Our work identifies a role for Akt in lumenogenesis and the significance of the R-Ras-Akt signaling for the patency of regenerating blood vessels.
内皮管腔的形成对于血管生成至关重要，对于缺氧组织的氧合也必不可少。这个重要过程的分子机制仍然不清楚。在这里，我们表明，Ras 同源物 R-Ras 激活 Akt 可稳定内皮细胞中的微管细胞骨架，从而导致内皮管腔发生。强力血管生成因子 VEGF-A 激活 Akt 并不能强烈稳定微管或充分促进管腔形成，因此证明了 R-Ras-Akt 轴的独特作用。我们在小鼠中表明，该途径对于缺血肌肉中新毛细血管和微血管的管腔化很重要，以允许在缺血损伤后进行足够的组织再灌注。我们的工作确定了 Akt 在管腔发生中的作用，以及 R-Ras-Akt 信号对于再生血管通畅性的重要性。
