Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2.
In the face of systemic risk factors, certain regions of the arterial vasculature remain relatively resistant to the development of atherosclerotic lesions. The biomechanically distinct environments in these arterial geometries exert a protective influence via certain key functions of the endothelial lining; however, the mechanisms underlying the coordinated regulation of specific mechano-activated transcriptional programs leading to distinct endothelial functional phenotypes have remained elusive. Here, we show that the transcription factor Kruppel-like factor 2 (KLF2) is selectively induced in endothelial cells exposed to a biomechanical stimulus characteristic of atheroprotected regions of the human carotid and that this flow-mediated increase in expression occurs via a MEK5/ERK5/MEF2 signaling pathway. Overexpression and silencing of KLF2 in the context of flow, combined with findings from genome-wide analyses of gene expression, demonstrate that the induction of KLF2 results in the orchestrated regulation of endothelial transcriptional programs controlling inflammation, thrombosis/hemostasis, vascular tone, and blood vessel development. Our data also indicate that KLF2 expression globally modulates IL-1beta-mediated endothelial activation. KLF2 therefore serves as a mechano-activated transcription factor important in the integration of multiple endothelial functions associated with regions of the arterial vasculature that are relatively resistant to atherogenesis.
Parmar
Kush M
KM
Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Larman
H Benjamin
HB
Dai
Guohao
G
Zhang
Yuzhi
Y
Wang
Eric T
ET
Moorthy
Sripriya N
SN
Kratz
Johannes R
JR
Lin
Zhiyong
Z
Jain
Mukesh K
MK
Gimbrone
Michael A
MA
García-Cardeña
Guillermo
G
D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014471:Umbilical Veins
D017931:DNA Primers; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D034741:RNA, Small Interfering