KLF2 and KLF4 control endothelial identity and vascular integrity

Sangwung, Panjamaporn; Zhou, Guangjin; Nayak, Lalitha; Chan, E. Ricky; Kumar, Sandeep; Kang, Dong‐Won; Zhang, Rongli; Liao, Xudong; Lü, Yuan; Sugi, Keiki; Fujioka, Hisashi; Shi, Hong; Lapping, Stephanie; Ghosh, Chandra C.; Higgins, Sarah J.; Parikh, Samir M.; Jo, Hanjoong; Jain, Mukesh K.

doi:10.1172/jci.insight.91700

Cited by 175 publications

(185 citation statements)

References 36 publications

(42 reference statements)

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“…Increases in KLF2 and KLF4 mRNA expression were also confirmed in HCAECs (Figure S1, A and B). As a positive control, 18 mRNA expression of NOS3 was examined and found to be significantly enhanced (Figure 1A). Further, the effect of KLF2 or KLF4 deficiency on Hba mRNA expression was examined in ECs isolated from adult mice with tamoxifen-inducible endothelial Klf2 (EC- Klf2 -KO), Klf4 (EC- Klf4 -KO), or both Klf2 and Klf4 (EC-DKO) knockout.…”

Section: Resultsmentioning

confidence: 99%

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Regulation of endothelial hemoglobin alpha expression by Kruppel-like factors

et al. 2017

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Hemoglobin subunit alpha (HBA) expression in endothelial cells (ECs) has recently been shown to control vascular tone and function. We sought to elucidate the transcriptional regulation of HBA expression in the EC. Gain of KLF2 or KLF4 function studies led to significant induction of HBA in ECs. An opposite effect was observed in ECs isolated from animals with endothelial-specific ablation of Klf2, Klf4 or both. Promoter reporter assays demonstrated that KLF2/KLF4 transactivated the hemoglobin alpha promoter, an effect that was abrogated following mutation of all four putative KLF-binding sites. Fine promoter mutational studies localized three out of four KLF-binding sites (sites 2, 3, and 4) as critical for the transactivation of the HBA promoter by KLF2/KLF4. Chromatin immunoprecipitation studies showed that KLF4 bound to the HBA promoter in ECs. Thus, KLF2 and KLF4 serve as important regulators that promote HBA expression in the endothelium.

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Section: Resultsmentioning

confidence: 99%

“…16–18 KLFs are members of the zinc-finger family of DNA-binding transcription factors, of which a total of 18 mammalian family members have been identified to date. 19 In ECs, KLF2 and KLF4 are induced by laminar flow and regulate the expression of many flow-dependent endothelial gene products (e.g.…”

Section: Introductionmentioning

confidence: 99%

Regulation of endothelial hemoglobin alpha expression by Kruppel-like factors

et al. 2017

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“…Not surprisingly, we also found sites for NRF1/2, which is essential for diabetes-dependent reduced expression of key genes in oxidative metabolism and mitochondrial function (44) (highlighted in yellow, Supplemental Table 4). Utilizing in vitro and in vivo model systems, it has previously been demonstrated that SP1 and KLF2/4 directly regulate Nos3 by binding to its promoter (45,46). Closer examination of the Nos3 locus revealed a decrease in ATAC-seq signal with HG stress compared with NG ( Figure 3D).…”

Section: Introductionmentioning

confidence: 88%

Epigenetic mechanisms underlying maternal diabetes-associated risk of congenital heart disease

et al. 2017

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“…The four Mef2s (Mef2a - d) are important transcriptional regulators in a number of cell types that can activate or repress transcription depending on modifications and interacting partners 12–14 . The most studied in vitro targets for Mef2 in ECs are Klf2 and Klf4, which regulate an anti-thrombotic and anti-inflammatory transcriptional program 15–21 . Two stimuli that protect against atherosclerosis increase the ability of Mef2 to activate transcription in vitro: LF and statins.…”

Section: Introductionmentioning

confidence: 99%

Endothelial Myocyte Enhancer Factor 2c Inhibits Migration of Smooth Muscle Cells Through Fenestrations in the Internal Elastic Lamina

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Sun

et al. 2017

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Objective Laminar flow activates MEF2 transcription factors in vitro to induce expression of atheroprotective genes in the endothelium. Here we sought to establish the role of Mef2c in the vascular endothelium in vivo. Approach and Results To study endothelial Mef2c, we generated endothelial-specific deletion of Mef2c using Tie2-Cre or Cdh5-Cre-ERT2 and examined aortas and carotid arteries by en face immunofluorescence. We observed enhanced actin stress fiber formation in the Mef2c-deleted thoracic aortic endothelium (laminar flow region), similar to those observed in normal aortic inner curvature (disturbed flow region). Furthermore, Mef2c deletion resulted in the de novo formation of subendothelial intimal cells expressing markers of differentiated smooth muscle in the thoracic aortas and carotids. Lineage-tracing showed that these cells were not of endothelial origin. To define early events in intimal development, we induced endothelial deletion of Mef2c and examined aortas at 4 and 12 weeks post induction. The number of intimal cell clusters increased from 4 to 12 weeks, but the number of cells within a cluster peaked at 2 cells in both cases, suggesting ongoing migration but minimal proliferation. Moreover, we identified cells extending from the media through fenestrations in the internal elastic lamina into the intima, indicating trans-fenestral smooth muscle migration. Similar trans-fenestral migration was observed in wild-type carotid arteries ligated to induce neointimal formation. Conclusions These results indicate that endothelial Mef2c regulates the endothelial actin cytoskeleton and inhibits smooth muscle cell migration into the intima.

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KLF2 and KLF4 control endothelial identity and vascular integrity

Cited by 175 publications

References 36 publications

Regulation of endothelial hemoglobin alpha expression by Kruppel-like factors

Regulation of endothelial hemoglobin alpha expression by Kruppel-like factors

Epigenetic mechanisms underlying maternal diabetes-associated risk of congenital heart disease

Endothelial Myocyte Enhancer Factor 2c Inhibits Migration of Smooth Muscle Cells Through Fenestrations in the Internal Elastic Lamina

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