Sickle cell disease (SCD) is canonically characterized by reduced red blood cell (RBC) deformability, leading to microvascular obstruction and inflammation. Although the biophysical properties of sickle RBCs are known to influence SCD vasculopathy, the contribution of poor RBC deformability to endothelial dysfunction has yet to be fully explored. Leveraging interrelated in vitro and in silico approaches, we introduce a new paradigm of SCD vasculopathy in which poorly deformable sickle RBCs directly cause endothelial dysfunction via mechanotransduction, during which endothelial cells sense and pathophysiologically respond to aberrant physical forces independently of microvascular obstruction, adhesion, or hemolysis. We demonstrate that perfusion of sickle RBCs or pharmacologically-dehydrated healthy RBCs into small venule-sized “endothelialized” microfluidics leads to pathologic physical interactions with endothelial cells that directly induce inflammatory pathways. Using a combination of computational simulations and large venule-sized endothelialized microfluidics, we observed that perfusion of heterogeneous sickle RBC subpopulations with varying deformability, as well as suspensions of dehydrated normal RBCs admixed with normal RBCs, leads to aberrant margination of the less-deformable RBC subpopulations toward the vessel walls, causing localized, increased shear stress. Increased wall stress is dependent on the degree of subpopulation heterogeneity and oxygen tension and leads to inflammatory endothelial gene expression via mechanotransductive pathways. Our multifaceted approach demonstrates that the presence of sickle RBCs with reduced deformability leads directly to pathological physical (ie, direct collisions and/or compressive forces) and shear-mediated interactions with endothelial cells and induces an inflammatory response, thereby elucidating the ubiquity of vascular dysfunction in SCD.

中文翻译：

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在镰状细胞病中，不易变形的红细胞亚群在生物力学上诱导内皮炎症


镰状细胞病 （SCD） 的典型特征是红细胞 （RBC） 变形能力降低，导致微血管阻塞和炎症。尽管已知镰状红细胞的生物物理特性会影响 SCD 血管病变，但红细胞变形能力差对内皮功能障碍的影响尚未得到充分探索。利用相互关联的体外和计算机方法，我们引入了一种新的 SCD 血管病变范式，其中变形不良的镰状红细胞通过机械转导直接导致内皮功能障碍，在此期间，内皮细胞对异常物理力的感觉和病理生理反应独立于微血管阻塞、粘附或溶血。我们证明，镰状红细胞或药理学脱水的健康红细胞灌注到小静脉大小的“内皮化”微流体中会导致与直接诱导炎症通路的内皮细胞发生病理性物理相互作用。使用计算模拟和大小静脉大小的内皮化微流体相结合，我们观察到具有不同变形性的异质镰状红细胞亚群的灌注，以及脱水的正常红细胞与正常红细胞混合的悬浮液，导致变形性较差的红细胞亚群向血管壁的边缘异常化，导致局部、剪切应力增加。壁应力增加取决于亚群异质性和氧紧张程度，并通过机械转导途径导致炎性内皮基因表达。 我们的多方面方法表明，变形性降低的镰状红细胞的存在直接导致病理性物理（即直接碰撞和/或压缩力）和剪切介导的与内皮细胞的相互作用，并诱导炎症反应，从而阐明 SCD 中血管功能障碍的普遍性。