Hypoxia induces dilated cardiomyopathy in the chick embryo: mechanism, intervention, and long-term consequences.
BACKGROUND
Intrauterine growth restriction is associated with an increased future risk for developing cardiovascular diseases. Hypoxia in utero is a common clinical cause of fetal growth restriction. We have previously shown that chronic hypoxia alters cardiovascular development in chick embryos. The aim of this study was to further characterize cardiac disease in hypoxic chick embryos.


METHODS
Chick embryos were exposed to hypoxia and cardiac structure was examined by histological methods one day prior to hatching (E20) and at adulthood. Cardiac function was assessed in vivo by echocardiography and ex vivo by contractility measurements in isolated heart muscle bundles and isolated cardiomyocytes. Chick embryos were exposed to vascular endothelial growth factor (VEGF) and its scavenger soluble VEGF receptor-1 (sFlt-1) to investigate the potential role of this hypoxia-regulated cytokine.


RESULTS
Growth restricted hypoxic chick embryos showed cardiomyopathy as evidenced by left ventricular (LV) dilatation, reduced ventricular wall mass and increased apoptosis. Hypoxic hearts displayed pump dysfunction with decreased LV ejection fractions, accompanied by signs of diastolic dysfunction. Cardiomyopathy caused by hypoxia persisted into adulthood. Hypoxic embryonic hearts showed increases in VEGF expression. Systemic administration of rhVEGF(165) to normoxic chick embryos resulted in LV dilatation and a dose-dependent loss of LV wall mass. Lowering VEGF levels in hypoxic embryonic chick hearts by systemic administration of sFlt-1 yielded an almost complete normalization of the phenotype.


CONCLUSIONS
Our data show that hypoxia causes a decreased cardiac performance and cardiomyopathy in chick embryos, involving a significant VEGF-mediated component. This cardiomyopathy persists into adulthood.
Laboratory for Angiogenesis and Cardiovascular Pathology, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany.
Andrei
A
Tintu
Ellen
E
Rouwet
Stefan
S
Verlohren
Joep
J
Brinkmann
Shakil
S
Ahmad
Fatima
F
Crispi
Marc
M
van Bilsen
Peter
P
Carmeliet
Anne Cathrine
AC
Staff
Marc
M
Tjwa
Irene
I
Cetin
Eduard
E
Gratacos
Edgar
E
Hernandez-Andrade
Leo
L
Hofstra
Michael
M
Jacobs
Wouter H
WH
Lamers
Ingo
I
Morano
Erdal
E
Safak
Asif
A
Ahmed
Ferdinand
F
le Noble
D000818:Animals; D017209:Apoptosis; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000503:physiopathology / Q000628:therapy; D002642:Chick Embryo / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D002645:Chickens; D064211:Connectin; D004452:Echocardiography; D005317:Fetal Growth Retardation / Q000209:etiology / Q000503:physiopathology; D006321:Heart / Q000033:anatomy & histology / Q000196:embryology; D006330:Heart Defects, Congenital / Q000209:etiology*; D006801:Humans; D000860:Hypoxia / Q000150:complications / Q000503:physiopathology; D009124:Muscle Proteins / Q000378:metabolism; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure; D011494:Protein Kinases / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D016277:Ventricular Function, Left
D064211:Connectin; D009124:Muscle Proteins; C577285:TTN protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D011494:Protein Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1