The ATX–LPA Axis Regulates Vascular Permeability during Cerebral Ischemic-Reperfusion

International Journal of Molecular Sciences

Susmita Bhattarai¹  Sudha Sharma¹  Utsab Subedi¹  Hosne Ara¹  Murov Milena¹  Manikandan Panchatcharam¹  Sumitra Miriyala¹  Alika Shum¹  Hong Sun¹  Srivatsan Kidambi²  Md. Shenuarin Bhuiyan³ 

[1] Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences, Shreveport, LA 71103, USA;Department of Chemical and Biomolecular Engineering, University of Nebraska, Lincoln, NB 68588, USA;Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences, Shreveport, LA 71103, USA;

关键词: lysophosphatidic acid;    autotaxin;    permeability;    ischemic-reperfusion;    blood–brain barrier;   

DOI  :  10.3390/ijms23084138

来源: DOAJ

【 摘 要 】

Endothelial permeability is a major complication that must be addressed during stroke treatment. Study of the mechanisms underlying blood–brain barrier (BBB) disruption and management of the hypoxic stress-induced permeability of the endothelium following reperfusion are both urgently needed for stroke management. Lysophosphatidic acid (LPA), a bioactive lipid essential for basic cellular functions, causes unfavorable outcomes during stroke progression. LPA-producing enzyme autotaxin (ATX) is regulated in ischemic stroke. We used an electrical cell-substrate impedance sensor (ECIS) to measure endothelial permeability. Mitochondrial bioenergetics were obtained using a Seahorse analyzer. AR-2 probe fluorescence assay was used to measure ATX activity. LPA increased endothelial permeability and reduced junctional protein expression in mouse brain microvascular endothelial cells (MBMEC). LPA receptor inhibitors Ki16425 and AM095 attenuated the LPA-induced changes in the endothelial permeability and junctional proteins. LPA significantly diminished mitochondrial function in MBMEC. ATX was upregulated (p < 0.05) in brain microvascular endothelial cells under hypoxic reperfusion. ATX activity and permeability were attenuated with the use of an ATX inhibitor in a mouse stroke model. The upregulation of ATX with hypoxic reperfusion leads to LPA production in brain endothelial cells favoring permeability. Inhibition of the ATX–LPA–LPAR axis could be therapeutically targeted in stroke to achieve better outcomes.

【 授权许可】

Unknown