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Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2
Kush M. Parmar, … , Michael A. Gimbrone Jr., Guillermo García-Cardeña
Kush M. Parmar, … , Michael A. Gimbrone Jr., Guillermo García-Cardeña
Published January 4, 2006
Citation Information: J Clin Invest. 2006;116(1):49-58. https://doi.org/10.1172/JCI24787.
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Research Article Cardiology Article has an altmetric score of 6

Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2

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Abstract

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-1β–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.

Authors

Kush M. Parmar, H. Benjamin Larman, Guohao Dai, Yuzhi Zhang, Eric T. Wang, Sripriya N. Moorthy, Johannes R. Kratz, Zhiyong Lin, Mukesh K. Jain, Michael A. Gimbrone Jr., Guillermo García-Cardeña

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Figure 1

Flow-dependent expression of KLF2 and its regulation by a MEK5/ERK5/MEF2 pathway.

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Flow-dependent expression of KLF2 and its regulation by a MEK5/ERK5/MEF2...
(A) Archetypal atheroprotective and atheroprone shear stress waveforms derived from a human carotid artery, as previously described (4). These 2 shear stress waveforms were recreated using a dynamic flow system and applied to cultured HUVECs. (B) HUVECs were cultured under static (no flow), atheroprone, or atheroprotective flow conditions for 24 hours, and KLF2 mRNA expression was measured by RT-PCR (n = 3; mean ± SEM). (C) Whole-mount in situ hybridization of WT or sih mutant embryos at 48 hours, probed for Flk or KLF2a. Inserts show close-ups of the trunk vasculature. Anal sphincter staining is indicated by arrowheads. (D) ChIP of MEF2A and MEF2C with the KLF2 promoter under static conditions and flow. (E) KLF2 mRNA in HUVECs infected with control (GFP) or dominant negative MEF2 (MEF2ASA) adenovirus 24 hours before exposure to the static (no flow) or atheroprotective waveform. (F) Western blot of total immunoprecipitated ERK5 and p-ERK5 from HUVECs under static or flow 24 hours after infection with control (GFP) or MEK5-DN adenovirus. (G) KLF2 mRNA levels from experimental samples represented in F. (H) Western blot of ERK5 immunoprecipitates under conditions described in F from HUVECs infected with GFP or MEK5-CA adenovirus. (I) KLF2 mRNA from samples represented in H. *P < 0.05, **P < 0.01 vs. control; Student’s t test. ctrl, control.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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