KLF2 and KLF4 control endothelial identity and vascular integrity
Panjamaporn Sangwung, … , Hanjoong Jo, Mukesh K. Jain
Panjamaporn Sangwung, … , Hanjoong Jo, Mukesh K. Jain
Published February 23, 2017
Citation Information: JCI Insight. 2017;2(4):e91700. https://doi.org/10.1172/jci.insight.91700.
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Research Article Vascular biology

KLF2 and KLF4 control endothelial identity and vascular integrity

Abstract

Maintenance of vascular integrity in the adult animal is needed for survival, and it is critically dependent on the endothelial lining, which controls barrier function, blood fluidity, and flow dynamics. However, nodal regulators that coordinate endothelial identity and function in the adult animal remain poorly characterized. Here, we show that endothelial KLF2 and KLF4 control a large segment of the endothelial transcriptome, thereby affecting virtually all key endothelial functions. Inducible endothelial-specific deletion of Klf2 and/or Klf4 reveals that a single allele of either gene is sufficient for survival, but absence of both (EC-DKO) results in acute death from myocardial infarction, heart failure, and stroke. EC-DKO animals exhibit profound compromise in vascular integrity and profound dysregulation of the coagulation system. Collectively, these studies establish an absolute requirement for KLF2/4 for maintenance of endothelial and vascular integrity in the adult animal.

Authors

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

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Figure 3

Endothelial-specific Klf2 and Klf4 deletion results in profound alterations in the EC transcriptome.

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Endothelial-specific Klf2 and Klf4 deletion results in profound alterati...
(A) A volcano plot showing 6,094 significantly differentially expressed genes (red dots indicate q < 0.05) in primary cardiac microvascular endothelial cells (EC) obtained from EC-DKO mice when compared with CRE mice. Significantly differentially expressed genes were determined by Cuffdiff. (B) Heatmap of the top 200 genes differentially expressed in primary cardiac microvascular ECs of CRE and EC-DKO mice (n = 4 per genotype, each n was pooled from 2 mice). (C) Normalized enrichment score (NES) represents the distribution of 28 of the 50 hallmark gene pathways. Positive and negative values indicate upregulation of genes in the CRE mice in comparison to EC-DKO mice and upregulation of genes in EC-DKO mice relative to CRE mice, respectively. CRE, Cdh5(PAC)-Ert2cre; EC-DKO, EC-specific Klf2 and Klf4 double knockout.