Klf2 is an essential regulator of vascular hemodynamic forces in vivo.
Hemodynamic responses that control blood pressure and the distribution of blood flow to different organs are essential for survival. Shear forces generated by blood flow regulate hemodynamic responses, but the molecular and genetic basis for such regulation is not known. The transcription factor KLF2 is activated by fluid shear stress in cultured endothelial cells, where it regulates a large number of vasoactive endothelial genes. Here, we show that Klf2 expression during development mirrors the rise of fluid shear forces, and that endothelial loss of Klf2 results in lethal embryonic heart failure due to a high-cardiac-output state. Klf2 deficiency does not result in anemia or structural vascular defects, and it can be rescued by administration of phenylephrine, a catecholamine that raises vessel tone. These findings identify Klf2 as an essential hemodynamic regulator in vivo and suggest that hemodynamic regulation in response to fluid shear stress is required for cardiovascular development and function.
Lee
John S
JS
Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Yu
Qing
Q
Shin
Jordan T
JT
Sebzda
Eric
E
Bertozzi
Cara
C
Chen
Mei
M
Mericko
Patti
P
Stadtfeld
Matthias
M
Zhou
Diane
D
Cheng
Lan
L
Graf
Thomas
T
MacRae
Calum A
CA
Lepore
John J
JJ
Lo
Cecilia W
CW
Kahn
Mark L
ML
D000740:Anemia / Q000503:physiopathology; D000818:Animals; D001165:Arteriovenous Malformations / Q000503:physiopathology; D001783:Blood Flow Velocity; D001808:Blood Vessels / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004625:Embryo, Nonmammalian; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D005804:Genes, Lethal; D006333:Heart Failure; D019426:Integrases / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000502:physiology; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D042787:Receptor, TIE-2 / Q000235:genetics / Q000502:physiology; D013314:Stress, Mechanical; D014158:Transcription, Genetic; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism
C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D008840:Microfilament Proteins; D009124:Muscle Proteins; C051615:transgelin; D010656:Phenylephrine; D042787:Receptor, TIE-2; C045073:Cre recombinase; D019426:Integrases