Kruppel-Like Factor 2 Regulates Endothelial Barrier Function

Abstract

Objective A central function of the endothelium is to serve as a selective barrier that regulates fluid and solute exchange. While perturbation of barrier function can contribute to numerous disease states, our understanding of the molecular mechanisms regulating this aspect of endothelial biology remains incompletely understood. Accumulating evidence implicates the Kruppel-like factor 2 (KLF2) as a key regulator of endothelial function. However, its role in vascular barrier function is unknown. Methods and Results To assess the role of KLF2 in vascular barrier function in vivo, we measured the leakage of Evans Blue dye into interstitial tissues of the mouse ear after treatment with mustard oil. By comparison to KLF2+/+ mice, KLF2+/− mice exhibited a significantly higher degree of vascular leak. In accordance with our in vivo observation, adenoviral overexpression of KLF2 in HUVECs strongly attenuated the increase of endothelial leakage by thrombin and H2O2 as measured by FITC-Dextran passage. Conversely, KLF2 deficiency in HUVECs and primary endothelial cells derived from KLF2+/− mice exhibited a marked increase in thrombin and H2O2-induced permeability. Mechanistically, our studies indicate that KLF2 confers barrier-protection via differential effects on the expression of key junction protein occludin and modification of a signaling molecule (myosin light chain) that regulate endothelial barrier integrity. Conclusions These observations identify KLF2 as a novel transcriptional regulator of vascular barrier function.

FBW7 regulates endothelial functions by targeting KLF2 for ubiquitination and degradation

“…These data suggested that FBW7 affects leukocyte adhesion through KLF2. KLF2 is also a key regulator of endothelial barrier integrity [13]. The results of our dextran leakage assay showed that the knockdown of FBW7 reduced thrombininduced endothelial leakage, which could be rescued by KLF2 knockdown ( Figure 5F and Supplementary in- FBW7 reduced the inhibitory effect of KLF2 on angiogenesis.…”

“…Among them, KLF2 (also known as LKLF) is a central regulator of endothelial functions, including angiogenesis, inflammation, thrombosis and vascular tone [7,12]. A KLF2 deficiency impairs endothelial barrier integrity and increases endothelial leakage by regulating the expression of the key junction protein occludin [7,13]. The ectopic expression of KLF2 inhibits endothelial cell migration and angiogenesis by downregulating VEGFR2 [14].…”

Dopamine stabilizes tumor blood vessels by up-regulating angiopoietin 1 expression in pericytes and Krüppel-like factor-2 expression in tumor endothelial cells

“…Since KLF2 plays a prominent role in preventing vascular leakage, and because KLF2 can inhibit hydrogen peroxide (H 2 O 2 )-induced permeability in HUVEC, we investigated the effect of DA treatment on H 2 O 2 -induced permeability in these cells (SI Results and Fig. S7) (51). is absolutely necessary for KLF2-mediated endothelial cell homeostasis, we investigated the effect of DA on ERK5 function and its correlation with DA-induced KLF2 expression in endothelial cells (SI Results and Fig.…”

Reduced Krüppel-Like Factor 2 Aggravates Glomerular Endothelial Cell Injury and Kidney Disease in Mice with Unilateral Nephrectomy

“…3e9 Among KLF proteins, KLF2 is a key regulator of vascular hemodynamic forces in vivo 10 and mediates flowdependent phenotype in endothelial cells. 3,11 KLF2 has been shown to be essential in maintenance of endothelial integrity in adult mice 12 as well as in mouse embryonic vasculature. 13 KLF2 inhibits vascular endothelial growth factor (VEGF)-Aemediated angiogenesis 14 and regulates endothelial thrombotic function.…”