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 1

Endothelial-specific Klf2 and Klf4 deletion leads to rapid death of adult mice.

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Endothelial-specific Klf2 and Klf4 deletion leads to rapid death of adul...
(A) Survival curve of tamoxifen-induced endothelial-specific Klf2 and/or Klf4 gene deletion in adult mice. n = 37 EC-specific Klf2 and Klf4 double knockout (EC-DKO); n = 14 Cdh5(PAC)-Ert2cre (CRE); n = 19 EC-specific Klf2 knockout (EC-Klf2-KO); n = 13 EC-specific Klf4 knockout (EC-Klf4-KO), n = 8 EC-specific knockout of Klf4 plus one allele of Klf2 (EC-Klf4-KO/Klf2+/–); n = 11, EC-specific knockout of Klf2 plus one allele of Klf4 mice (EC-Klf2-KO/Klf4+/–). (B) Reduction of heart rate and (C) ST wave segment elevation were observed in EC-DKO mice (n = 4–5 per genotype). (D) Fractional shortening (FS), ejection fraction (EF), and cardiac output (CO) in CRE (n = 3) and EC-DKO mice (n = 5) at day 6 after tamoxifen. (E) Circulating cardiac troponin I level (n = 11–16 per genotype) and (F) representative images of TUNEL staining in the heart showing massive cardiomyocyte death in EC-DKO mice at day 6 after tamoxifen (n = 3 per genotype). Scale bar: 100 μm. (G) Representative gross anatomy images of brain, lungs, heart, and subcutaneous tissues at day 6 after tamoxifen indicate spontaneous hemorrhage in EC-DKO mice (n = 3–4 per genotype). EC, endothelial cell. Data are presented as mean ± SEM values. *P < 0.05, **P < 0.01. 2-tailed Student’s t test.