Kruppel-like factor 2 regulates endothelial barrier function.
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.


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, KLF2(+/-) 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 H(2)O(2) 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 H(2)O(2)-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.
Lin
Zhiyong
Z
University Hospitals Harrington-McLaughlin Heart and Vascular Institute and Case Cardiovascular Research Institute, Cleveland, OH 44106-7290, USA. zhiyong.lin@case.edu
Natesan
Viswanath
V
Shi
Hong
H
Dong
Fei
F
Kawanami
Daiji
D
Mahabeleshwar
Ganapati H
GH
Atkins
G Brandon
GB
Nayak
Lalitha
L
Cui
Yingjie
Y
Finigan
James H
JH
Jain
Mukesh K
MK
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D018994:Myosin Light Chains / Q000502:physiology; D062793:Occludin; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology; D014162:Transfection
C096161:KLF2 protein, human; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D018994:Myosin Light Chains; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D006861:Hydrogen Peroxide; D013917:Thrombin