Kruppel-Like Factor Regulation in Endothelial Biology

The Kruppel-like factors (KLFs) comprise a family of zinc-finger transcription factors that orchestrate endothelial gene programmes central to vessel homeostasis, inflammation and angiogenesis. Prominent members such as KLF2, KLF4 and KLF11 are activated by biomechanical and biochemical stimuli to maintain a vasculoprotective phenotype. Under steady laminar flow, KLF2 and KLF4 are induced via the MEK5–ERK5–MEF2 axis, leading to enhanced nitric oxide synthesis, reduced leukocyte adhesion and attenuated oxidative stress. These factors also interface with canonical pathways such as NF-κB and Notch to balance endothelial quiescence, sprouting and barrier integrity. Dysregulation of KLF expression under pro-inflammatory or hyperglycaemic conditions contributes to endothelial-to-mesenchymal transition, pro-thrombotic shifts and accelerated atherogenesis. Restoration of KLF activity through pharmacological agents, genetic approaches or rheological interventions has demonstrated promise in preclinical models of atherosclerosis, diabetic vascular dysfunction and chronic kidney disease. Collectively, KLF regulation in endothelium represents a convergent node for mechanotransduction and metabolic cues, offering therapeutic avenues for cardiovascular and metabolic disorders.

Research from Nature Portfolio

High-throughput screening has identified tannic acid as a potent inducer of endothelial KLF2 expression through the ERK5–MEF2 pathway, resulting in marked reduction of monocyte adhesion and adhesion molecule expression. Mechanistic studies in murine and human cells reveal that the anti-inflammatory efficacy of this polyphenolic treatment is contingent on KLF2 function, underscoring the potential of dietary compounds to modulate transcriptional networks. In parallel, investigations into shear stress-responsive transcripts have highlighted peptidase inhibitor 16 (PI16) as a key mediator of protease inhibition in human coronary endothelium. Overexpression of PI16 attenuates matrix metalloproteinase-2 activity and endothelial migration during inflammation, providing new insight into how shear-induced KLF targets contribute to vascular stabilisation under disturbed flow.

Kruppel-Like Factor Regulation in Endothelial Biology publication trend

The graph below shows the total number of articles in kruppel-like factor regulation in endothelial biology across all publications each year (not limited to Nature Index journals).

Technical terms

Transcription factor: A protein that binds to specific DNA sequences to regulate gene expression.

Endothelial-to-mesenchymal transition (EndMT): A process by which endothelial cells acquire mesenchymal characteristics, contributing to fibrosis and vascular remodelling.

Shear stress: The frictional force exerted by blood flow on the endothelial surface, influencing gene expression and vascular tone.

Vasculoprotective phenotype: An endothelial state characterised by anti-inflammatory, anti-thrombotic and antioxidant properties.

MEF2 (Myocyte Enhancer Factor 2): A family of transcription factors that cooperate with ERK5 to induce KLF expression under laminar flow.

References

1. Endothelial KLF11 is a novel protector against diabetic atherosclerosis. Cardiovascular Diabetology (2024).
2. Expanded Hemodialysis ameliorates uremia-induced impairment of vasculoprotective KLF2 and concomitant proinflammatory priming of endothelial cells through an ERK/AP1/cFOS-dependent mechanism. Frontiers in Immunology (2023).
3. Dysregulation of Krüppel-like Factor 2 and Myocyte Enhancer Factor 2D Drive Cardiac Microvascular Inflammation and Dysfunction in Diabetes. International Journal of Molecular Sciences (2023).
4. KLF2 in Regulation of NF-κB-Mediated Immune Cell Function and Inflammation. International Journal of Molecular Sciences (2017).
5. Erk5 Activation Elicits a Vasoprotective Endothelial Phenotype via Induction of Krüppel-like Factor 4 (KLF4)*. Journal of Biological Chemistry (2010).
6. Endothelial Krüppel-like Factor 4 Regulates Angiogenesis and the Notch Signaling Pathway*. Journal of Biological Chemistry (2014).
7. Tannic acid as a plant-derived polyphenol exerts vasoprotection via enhancing KLF2 expression in endothelial cells. Scientific Reports (2017).
8. PI16 is a shear stress and inflammation-regulated inhibitor of MMP2. Scientific Reports (2016).