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

Susmita Bhattarai, Sudha Sharma, Utsab Subedi, Hosne Ara, Alika Shum, Murov Milena, Md Shenuarin Bhuiyan, Srivatsan Kidambi, Hong Sun, Sumitra Miriyala, Manikandan Panchatcharam

Research output: Contribution to journalArticlepeer-review

Abstract

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‐produc-ing 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 ac-tivity. 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 micro-vascular 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.

Original languageEnglish (US)
Article number4138
JournalInternational journal of molecular sciences
Volume23
Issue number8
DOIs
StatePublished - Apr 1 2022

Keywords

  • autotaxin
  • blood–brain barrier
  • ischemic‐reperfusion
  • lysophosphatidic acid
  • permeability

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Fingerprint

Dive into the research topics of 'The ATX–LPA Axis Regulates Vascular Permeability during Cerebral Ischemic‐Reperfusion'. Together they form a unique fingerprint.

Cite this