Endothelial Specific Deletion of Autotaxin Improves Stroke Outcomes.
Endothelial Specific Deletion of Autotaxin Improves Stroke Outcomes.
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作者：
自分泌运动因子（ATX）是一种细胞外分泌酶（溶血磷脂酶D），催化溶血磷脂酰胆碱水解为溶血磷脂酸（LPA）。ATX-LPA轴是肝纤维化、癌症转移、肺纤维化、动脉粥样硬化和神经退行性疾病的众所周知的病理介质。此外，据信LPA可引起血管渗透性。在缺血性卒中中，血管通透性导致出血性转化是治疗的主要限制和卒中管理的障碍。因此，在本研究中，我们在小鼠中产生了内皮特异性ATX缺失（ERT 2 ATX−/−），以观察小鼠卒中模型中的卒中结局，从而分析内皮ATX的作用。AR 2探针和伊文思蓝染色分别用于进行ATX活性和血管通透性测定。应用激光散斑成像技术观察脑卒中后的脑血流变化。在这项研究中，我们观察到ATX内皮缺失可减轻卒中结局。与仅缺血再灌注（I/R）小鼠相比，ERT 2 ATX−/−小鼠的渗透性和梗死体积减少。此外，与I/R小鼠相比，ERT 2 ATX−/−小鼠的脑血流量得以保留。由于ERT 2 ATX−/−小鼠中LPA浓度有限、ATX浓度降低和ATX活性降低，卒中模型中的结局得到缓解。这项研究表明，内皮特异性ATX导致缺血-再灌注后脑血管系统中LPA增加，并最终破坏血管通透性，导致不良卒中结局。
Autotaxin (ATX) is an extracellular secretory enzyme (lysophospholipase D) that catalyzes the hydrolysis of lysophosphatidyl choline to lysophosphatidic acid (LPA). The ATX–LPA axis is a well-known pathological mediator of liver fibrosis, metastasis in cancer, pulmonary fibrosis, atherosclerosis, and neurodegenerative diseases. Additionally, it is believed that LPA may cause vascular permeability. In ischemic stroke, vascular permeability leading to hemorrhagic transformation is a major limitation for therapies and an obstacle to stroke management. Therefore, in this study, we generated an endothelial-specific ATX deletion in mice (ERT2 ATX−/−) to observe stroke outcomes in a mouse stroke model to analyze the role of endothelial ATX. The AR2 probe and Evans Blue staining were used to perform the ATX activity and vascular permeability assays, respectively. Laser speckle imaging was used to observe the cerebral blood flow following stroke. In this study, we observed that stroke outcomes were alleviated with the endothelial deletion of ATX. Permeability and infarct volume were reduced in ERT2 ATX−/− mice compared to ischemia–reperfusion (I/R)-only mice. In addition, the cerebral blood flow was retained in ERT2 ATX−/− compared to I/R mice. The outcomes in the stroke model are alleviated due to the limited LPA concentration, reduced ATX concentration, and ATX activity in ERT2 ATX−/− mice. This study suggests that endothelial-specific ATX leads to increased LPA in the brain vasculature following ischemic–reperfusion and ultimately disrupts vascular permeability, resulting in adverse stroke outcomes.
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DOI：
10.2147/dddt.s56071
发表时间：
2015
期刊：
Drug design, development and therapy
影响因子：
--
作者：
Fluri F;Schuhmann MK;Kleinschnitz C
通讯作者：
Kleinschnitz C
影响因子：
11
作者：
Igarashi N;Honjo M;Yamagishi R;Kurano M;Yatomi Y;Igarashi K;Kaburaki T;Aihara M
通讯作者：
Aihara M
影响因子：
3
作者：
Kadar, Andrea;Wittmann, Gabor;Liposits, Zsolt;Fekete, Csaba
通讯作者：
Fekete, Csaba
影响因子：
5.6
作者：
Jose A;Kienesberger PC
通讯作者：
Kienesberger PC
影响因子：
37.8
作者：
Bouchareb, Rihab;Mahmut, Ablajan;Mathieu, Patrick
通讯作者：
Mathieu, Patrick