Embryonic heart failure in NFATc1-/- mice: novel mechanistic insights from in utero ultrasound biomicroscopy.
Gene targeting in the mouse has become a standard approach, yielding important new insights into the genetic factors underlying cardiovascular development and disease. However, we still have very limited understanding of how mutations affect developing cardiovascular function, and few studies have been performed to measure altered physiological parameters in mouse mutant embryos. Indeed, although in utero lethality due to embryonic heart failure is one of the most common results of gene targeting experiments in the mouse, the underlying physiological mechanisms responsible for embryonic demise remain elusive. Using in utero ultrasound biomicroscopy (UBM), we studied embryonic day (E) 10.5 to 14.5 NFATc1-/- embryos and control littermates. NFATc1-/- mice, which lack outflow valves, die at mid-late gestation from presumed defects in forward blood flow with resultant heart failure. UBM showed increasing abnormal regurgitant flow in the aorta and extending into the embryonal-placental circulation, which was evident after E12.5 when outflow valves normally first develop. Reduced NFATc1-/- net volume flow and diastolic dysfunction contributed to heart failure, but contractile function remained unexpectedly normal. Among 107 NFATc1-/- embryos imaged, only 2 were observed to be in acute decline with progressive bradyarrhythmia, indicating that heart failure occurs rapidly in individual NFATc1-/- embryos. This study is among the first linking a specific physiological phenotype with a defined genotype, and demonstrates that NFATc1-/- embryonic heart failure is a complex phenomenon not simply attributable to contractile dysfunction.
Phoon
Colin K L
CK
Pediatric Cardiology Program, New York University School of Medicine, New York, NY, USA. colin.phoon@med.nyu.edu
Ji
Rui Ping
RP
Aristizábal
Orlando
O
Worrad
Diane M
DM
Zhou
Bin
B
Baldwin
H Scott
HS
Turnbull
Daniel H
DH
D000818:Animals; D001775:Blood Circulation; D002303:Cardiac Output, Low / Q000000981:diagnostic imaging / Q000209:etiology* / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D004622:Embryo, Mammalian / Q000000981:diagnostic imaging / Q000503:physiopathology; D005260:Female; D005315:Fetal Diseases / Q000000981:diagnostic imaging / Q000209:etiology* / Q000503:physiopathology; D006321:Heart / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D033401:Microscopy, Acoustic; D009200:Myocardial Contraction; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000235:genetics*; D021041:Placental Circulation; D011247:Pregnancy; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors