Arpino John-Michael, Yin Hao, Prescott Emma K, Staples Sabrina C R, Nong Zengxuan, Li Fuyan, Chevalier Jacqueline, Balint Brittany, O'Neil Caroline, Mortuza Rokhsana, Milkovich Stephanie, Lee Jason J, Lorusso Daniel, Sandig Martin, Hamilton Douglas W, Holdsworth David W, Poepping Tamie L, Ellis Christopher G, Pickering J Geoffrey
Robarts Research Institute, Western University, London, Canada.
Department of Medical Biophysics, Western University, London, Canada.
Sci Adv. 2021 Nov 26;7(48):eabg9509. doi: 10.1126/sciadv.abg9509.
Efforts to promote sprouting angiogenesis in skeletal muscles of individuals with peripheral artery disease have not been clinically successful. We discovered that, contrary to the prevailing view, angiogenesis following ischemic muscle injury in mice was not driven by endothelial sprouting. Instead, real-time imaging revealed the emergence of wide-caliber, primordial conduits with ultralow flow that rapidly transformed into a hierarchical neocirculation by transluminal bridging and intussusception. This process was accelerated by inhibiting vascular endothelial growth factor receptor-2 (VEGFR2). We probed this response by developing the first live-cell model of transluminal endothelial bridging using microfluidics. Endothelial cells subjected to ultralow shear stress could reposition inside the flowing lumen as pillars. Moreover, the low-flow lumen proved to be a privileged location for endothelial cells with reduced VEGFR2 signaling capacity, as VEGFR2 mechanosignals were boosted. These findings redefine regenerative angiogenesis in muscle as an intussusceptive process and uncover a basis for its launch.
促进外周动脉疾病患者骨骼肌中芽生血管生成的努力在临床上尚未取得成功。我们发现，与普遍观点相反，小鼠缺血性肌肉损伤后的血管生成并非由内皮细胞芽生驱动。相反，实时成像显示出现了具有超低流量的宽口径原始管道，这些管道通过腔内桥接和套叠迅速转变为分层的新循环。抑制血管内皮生长因子受体2（VEGFR2）可加速这一过程。我们通过使用微流控技术开发首个腔内内皮桥接的活细胞模型来探究这种反应。受到超低剪切应力作用的内皮细胞可以作为支柱重新定位在流动的管腔内。此外，低流量管腔被证明是VEGFR2信号传导能力降低的内皮细胞的特殊位置，因为VEGFR2机械信号得到了增强。这些发现将肌肉中的再生血管生成重新定义为一个套叠过程，并揭示了其启动的基础。
