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

KM Parmar, HB Larman, G Dai, Y Zhang… - The Journal of …, 2006 - Am Soc Clin Investig
KM Parmar, HB Larman, G Dai, Y Zhang, ET Wang, SN Moorthy, JR Kratz, Z Lin, MK Jain
The Journal of clinical investigation, 2006Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation