ABSTRACT
Angiogenesis helps to improve neurological recovery by repairing damaged brain tissue
and restoring cerebral blood flow (CBF). The role of the Elabela (ELA)-Apelin receptor
(APJ) system in angiogenesis has gained much attention. We aimed to investigate the
function of endothelial ELA on postischemic cerebral angiogenesis. Here, we demonstrated
that the endothelial ELA expression was upregulated in the ischemic brain and treatment
with ELA-32 mitigated brain injury and enhanced the restoration of CBF and newly formed
functional vessels following cerebral ischemia/reperfusion (I/R) injury. Furthermore,
ELA-32 incubation potentiated proliferation, migration, and tube formation abilities
of the mouse brain endothelial cells (bEnd.3 cells) under oxygen-glucose deprivation/reoxygenation
(OGD/R) condition. RNA sequencing analysis indicated that ELA-32 incubation had a
role in the Hippo signaling pathway, and improved angiogenesis-related gene expression
in OGD/R-exposed bEnd.3 cells. Mechanistically, we depicted that ELA could bind to
APJ and subsequently activate YAP/TAZ signaling pathway. Silence of APJ or pharmacological
blockade of YAP abolished the pro-angiogenesis effects of ELA-32. Together, these
findings highlight the ELA-APJ axis as a potential therapeutic strategy for ischemic
stroke by showing how activation of this pathway promotes poststroke angiogenesis.
Keywords
Abbreviations:
ACA (Anterior cerebral artery), AIS (Acute ischemic stroke), ANG2 (Angiopoietin 2), APJ (Apelin receptor), CBF (Cerebral blood flow), CCA (Common carotid artery), CTGF (Connective tissue growth factor), CYR61 (Cysteine-rich 61), ECA (External carotid artery), ECs (Endothelial cells), ELA (Elabela), HUVECs (Human umbilical vein endothelial cells), I/R (Ischemia/Reperfusion), ICA (Internal carotid artery), MCA (Middle cerebral artery), MCAO (Middle cerebral artery occlusion), mNSS (Modified Neurological severity scoring), NOR (Novel object recognition), OGD/R (Oxygen-glucose deprivation/reoxygenation), PCA (Posterior cerebral artery), p-YAP (Phosphorylated-YAP), TAZ (Transcriptional co-activator with PDZ-binding motif), TEAD (Transcriptional enhancer associate domain), VSMCs (Vascular smooth muscle cells), YAP (Yes-associated protein)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: February 20, 2023
Accepted:
February 2,
2023
Received in revised form:
January 13,
2023
Received:
August 2,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Elsevier Inc. All rights reserved.
