title: Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2.
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-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.
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Kush M
authors.initials: KM
authors.lastname: Parmar
authors.forename: H Benjamin
authors.initials: HB
authors.lastname: Larman
authors.forename: Guohao
authors.initials: G
authors.lastname: Dai
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Eric T
authors.initials: ET
authors.lastname: Wang
authors.forename: Sripriya N
authors.initials: SN
authors.lastname: Moorthy
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Kratz
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Lin
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gimbrone
authors.forename: Guillermo
authors.initials: G
authors.lastname: García-Cardeña
mesh_terms: 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
chemical_list: D017931:DNA Primers; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D034741:RNA, Small Interfering