Tran Huy, Mittal Aditya, Sagi Varun, Luk Kathryn, Nguyen Aithanh, Gupta Mihir, Nguyen Julia, Lamarre Yann, Lei Jianxun, Guedes Alonso, Gupta Kalpna
Vascular Biology Center, Division of Hematology, Oncology and Transplantation, Department of Medicine, Medical School, University of Minnesota, Minneapolis, MN, United States.
Department of Neurosurgery, University of California, San Diego, San Diego, CA, United States.
Front Cell Neurosci. 2019 Feb 19;13:56. doi: 10.3389/fncel.2019.00056. eCollection 2019.
Endothelial dysfunction underlies the pathobiology of cerebrovascular disease. Mast cells are located in close proximity to the vasculature, and vasoactive mediators released upon their activation can promote endothelial activation leading to blood brain barrier (BBB) dysfunction. We examined the mechanism of mast cell-induced endothelial activation endoplasmic reticulum (ER) stress mediated P-selectin expression in a transgenic mouse model of sickle cell disease (SCD), which shows BBB dysfunction. We used mouse brain endothelial cells (mBECs) and mast cells-derived from skin of control and sickle mice to examine the mechanisms involved. Compared to control mouse mast cell conditioned medium (MCCM), mBECs incubated with sickle mouse MCCM showed increased, structural disorganization and swelling of the ER and Golgi, aggregation of ribosomes, ER stress marker proteins, accumulation of galactose-1-phosphate uridyl transferase, mitochondrial dysfunction, reactive oxygen species (ROS) production, P-selectin expression and mBEC permeability. These effects of sickle-MCCM on mBEC were inhibited by Salubrinal, a reducer of ER stress. Histamine levels in the plasma, skin releasate and in mast cells of sickle mice were higher compared to control mice. Compared to control BBB permeability was increased in sickle mice. Treatment of mice with imatinib, Salubrinal, or P-selectin blocking antibody reduced BBB permeability in sickle mice. Mast cells induce endothelial dysfunction ER stress-mediated P-selectin expression. Mast cell activation contributes to ER stress mediated endothelial P-selectin expression leading to increased endothelial permeability and impairment of BBB. Targeting mast cells and/or ER stress has the potential to ameliorate endothelial dysfunction in SCD and other pathobiologies.
内皮功能障碍是脑血管疾病病理生物学的基础。肥大细胞位于血管附近，其激活后释放的血管活性介质可促进内皮激活，导致血脑屏障（BBB）功能障碍。我们在镰状细胞病（SCD）的转基因小鼠模型中研究了肥大细胞诱导的内皮激活——内质网（ER）应激介导的P-选择素表达的机制，该模型表现出血脑屏障功能障碍。我们使用来自对照小鼠和镰状小鼠皮肤的小鼠脑内皮细胞（mBECs）和肥大细胞来研究其中涉及的机制。与对照小鼠肥大细胞条件培养基（MCCM）相比，用镰状小鼠MCCM孵育的mBECs显示出内质网和高尔基体结构紊乱、肿胀增加，核糖体聚集，内质网应激标记蛋白，1-磷酸半乳糖尿苷转移酶积累，线粒体功能障碍，活性氧（ROS）产生，P-选择素表达和mBEC通透性增加。镰状-MCCM对mBEC的这些作用被内质网应激抑制剂Salubrinal抑制。与对照小鼠相比，镰状小鼠血浆、皮肤释放物和肥大细胞中的组胺水平更高。与对照相比，镰状小鼠的血脑屏障通透性增加。用伊马替尼、Salubrinal或P-选择素阻断抗体治疗小鼠可降低镰状小鼠的血脑屏障通透性。肥大细胞诱导内皮功能障碍——内质网应激介导的P-选择素表达。肥大细胞激活导致内质网应激介导的内皮P-选择素表达增加，导致内皮通透性增加和血脑屏障受损。靶向肥大细胞和/或内质网应激有可能改善SCD和其他病理生物学中的内皮功能障碍。
