KLF4-Induced Connexin40 Expression Contributes to Arterial Endothelial Quiescence

Frontiers in Physiology
Jean-Francois DenisBrenda R Kwak

Abstract

Shear stress, a blood flow-induced frictional force, is essential in the control of endothelial cell (EC) homeostasis. High laminar shear stress (HLSS), as observed in straight parts of arteries, assures a quiescent non-activated endothelium through the induction of Krüppel-like transcription factors (KLFs). Connexin40 (Cx40)-mediated gap junctional communication is known to contribute to a healthy endothelium by propagating anti-inflammatory signals between ECs, however, the molecular basis of the transcriptional regulation of Cx40 as well as its downstream effectors remain poorly understood. Here, we show that flow-induced KLF4 regulated Cx40 expression in a mouse EC line. Chromatin immunoprecipitation in ECs revealed that KLF4 bound to three predicted KLF consensus binding sites in the Cx40 promoter. HLSS-dependent induction of Cx40 expression was confirmed in primary human ECs. The downstream effects of Cx40 modulation in ECs exposed to HLSS were elucidated by an unbiased transcriptomics approach. Cell cycle progression was identified as an important downstream target of Cx40 under HLSS. In agreement, an increase in the proportion of proliferating cell nuclear antigen (PCNA)-positive ECs and a decrease in the proportion of ...Continue Reading

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Citations

Aug 25, 2020·Circulation Research·Guy EelenPeter Carmeliet
May 4, 2020·Annals of Vascular Surgery·Christos BakoyiannisAlkistis Kapelouzou
Jun 4, 2021·Frontiers in Cardiovascular Medicine·David R SweetMukesh K Jain
Jul 25, 2021·Nature Communications·Pietro CacialliJulien Y Bertrand

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Datasets Mentioned

BETA
GSE118717

Methods Mentioned

BETA
transfections
PCR
protein assay
Immunoprecipitation
Chip
electrophoresis
RNAseq
transgenic
genotyping
LLSS

Software Mentioned

edgeR
ENSEMBL
R
ImageQuant LAS 4000
STAR
ImageJ
FlowJo
CellSens Dimensions
Zeiss Zen
Primer3

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