Annexin A1 as Neuroprotective Determinant for Blood-Brain Barrier Integrity in Neonatal Hypoxic-Ischemic Encephalopathy

Gussenhoven, Ruth, Luise Klein, Daan RMG Ophelders, Denise HJ Habets, Bernd Giebel, Boris W. Kramer, Leon J. Schurgers, Chris PM Reutelingsperger, and Tim GAM Wolfs. "Annexin A1 as Neuroprotective Determinant for Blood-Brain Barrier Integrity in Neonatal Hypoxic-Ischemic Encephalopathy." Journal of clinical medicine 8, no. 2 (2019): 137.

Abstract: Blood-brain barrier (BBB) disruption is associated with hypoxia-ischemia (HI) induced brain
injury and life-long neurological pathologies. Treatment options are limited. Recently, we found that
mesenchymal stem/stromal cell derived extracellular vesicles (MSC-EVs) protected the brain in ovine
fetuses exposed to HI. We hypothesized that Annexin A1 (ANXA1), present in MSC-EVs, contributed
to their therapeutic potential by targeting the ANXA1/Formyl peptide receptor (FPR), thereby
preventing loss of the BBB integrity. Cerebral ANXA1 expression and leakage of albumin into the fetal
ovine brain parenchyma after HI were analyzed by immunohistochemistry. For mechanistic insights,
barrier integrity of primary fetal endothelial cells was assessed after oxygen-glucose deprivation
(OGD) followed by treatment with MSC-EVs or human recombinant ANXA1 in the presence or
absence of FPR inhibitors. Our study revealed that BBB integrity was compromised after HI which
was improved by MSC-EVs containing ANXA1. Treatment with these MSC-EVs or ANXA1 improved
BBB integrity after OGD, an effect abolished by FPR inhibitors. Furthermore, endogenous ANXA1
was depleted within 24 h after induction of HI in cerebovasculature and ependyma and upregulated
72 h after HI in microglia. Targeting ANXA1/FPR with ANXA1 in the immature brain has great
potential in preventing BBB loss and concomitant brain injury following HI.
Keywords: Annexin A1/Formyl peptide receptor axis; blood-brain barrier; mesenchymal stem
cell-derived extracellular vesicles; neonatal hypoxia-ischemia; therapy

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