Cerebrovascular Angiogenic Reprogramming upon LRP1 Repression: Impact on Sphingosine-1-Phosphate-Mediated Signaling in Brain Endothelial Cell Chemotactism

Molecular Neurobiology
Amélie VézinaBorhane Annabi

Abstract

Switches in sphingolipid metabolism have recently been associated with oncogenic transformation, and a role for the low-density lipoprotein receptor-related protein 1 (LRP1) in sphingosine-1-phosphate (S1P) proangiogenic signaling inferred. S1P signaling crosstalk with LRP1 in brain microvascular endothelial cells (HBMEC) is however unclear. Transient in vitro siLRP1 gene silencing was compared to stable shLRP1 knockdown. We observed decreased expression of CCAAT/enhancer binding protein β (C/EBPβ), a transcription factor for which multiple binding sites are found within the promoter sequences of all five S1P receptor members, upon stable but not transient LRP1 repression. Chemotactic migration of brain EC isolated from Lrp1(EC)-/- mice and of stable shLRP1 HBMEC became unresponsive to S1P, partly due to altered ERK and p38 MAPK pathways, whereas chemotactism remained unaltered following transient in vitro siLRP1 repression. Diminished S1P1, S1P3, and S1P5 expression were observed in stable shLRP1 HBMEC and in brain EC isolated from Lrp1(EC)-/- mice. Overexpression of LRP1 cluster IV rescued S1P-mediated cell migration through increased S1P3 transcription in shLRP1 HBMEC. Our study highlights an adaptive signaling crosstalk bet...Continue Reading

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Citations

Feb 11, 2020·Frontiers in Neuroscience·Marco TjakraGuixue Wang
Aug 28, 2020·Frontiers in Oncology·Océane CampionJérôme Devy
Jan 8, 2021·Journal of Cellular Physiology·Xuehui FanGuozhong Li
Jul 11, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Zhaohui HeMao Luo

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Methods Mentioned

BETA
protein assay
transfection
flow cytometry
electrophoresis
gene knockdown
PCR
GTPases

Software Mentioned

GraphPad Prism
QuantiTect
Ensembl Genome Browser
RTCA DP Instrument
CFX ManagerTM

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