TY - JOUR
T1 - Kruppel-like factor 2 regulates endothelial barrier function
AU - Lin, Zhiyong
AU - Natesan, Viswanath
AU - Shi, Hong
AU - Dong, Fei
AU - Kawanami, Daiji
AU - Mahabeleshwar, Ganapati H.
AU - Atkins, G. Brandon
AU - Nayak, Lalitha
AU - Cui, Yingjie
AU - Finigan, James H.
AU - Jain, Mukesh K.
PY - 2010/10
Y1 - 2010/10
N2 - Objective-: A central function of the endothelium is to serve as a selective barrier that regulates fluid and solute exchange. Although 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 with KLF2+/- mice, KLF 2+/- mice exhibited a significantly higher degree of vascular leak. In accordance with our in vivo observation, adenoviral overexpression of KLF2 in human umbilical vein endothelial cells strongly attenuated the increase of endothelial leakage by thrombin and H2O2 as measured by fluorescein isothiocyanate dextrans (FITC-dextran) passage. Conversely, KLF2 deficiency in human umbilical vein endothelial cells 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. Conclusion-: These observations identify KLF2 as a novel transcriptional regulator of vascular barrier function.
AB - Objective-: A central function of the endothelium is to serve as a selective barrier that regulates fluid and solute exchange. Although 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 with KLF2+/- mice, KLF 2+/- mice exhibited a significantly higher degree of vascular leak. In accordance with our in vivo observation, adenoviral overexpression of KLF2 in human umbilical vein endothelial cells strongly attenuated the increase of endothelial leakage by thrombin and H2O2 as measured by fluorescein isothiocyanate dextrans (FITC-dextran) passage. Conversely, KLF2 deficiency in human umbilical vein endothelial cells 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. Conclusion-: These observations identify KLF2 as a novel transcriptional regulator of vascular barrier function.
KW - Kruppel-like factor 2
KW - barrier function
KW - endothelium
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U2 - 10.1161/ATVBAHA.110.211474
DO - 10.1161/ATVBAHA.110.211474
M3 - Article
C2 - 20651277
AN - SCOPUS:77957695484
SN - 1079-5642
VL - 30
SP - 1952
EP - 1959
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 10
ER -