A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function.
The role of the cardiac myocyte as a mediator of paracrine signaling in the heart has remained unclear. To address this issue, we generated mice with cardiac myocyte-specific deletion of the vascular endothelial growth factor gene, thereby producing a cardiomyocyte-specific knockout of a secreted factor. The hearts of these mice had fewer coronary microvessels, thinned ventricular walls, depressed basal contractile function, induction of hypoxia-responsive genes involved in energy metabolism, and an abnormal response to beta-adrenergic stimulation. These findings establish the critical importance of cardiac myocyte-derived vascular endothelial growth factor in cardiac morphogenesis and determination of heart function. Further, they establish an adult murine model of hypovascular nonnecrotic cardiac contractile dysfunction.
Giordano
F J
FJ
Cardiovascular Gene Therapy Program, Department of Medicine, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, Room 336C, New Haven, CT 06520, USA. Frank.Giordano@yale.edu
Gerber
H P
HP
Williams
S P
SP
VanBruggen
N
N
Bunting
S
S
Ruiz-Lozano
P
P
Gu
Y
Y
Nath
A K
AK
Huang
Y
Y
Hickey
R
R
Dalton
N
N
Peterson
K L
KL
Ross
J
J
Chien
K R
KR
Ferrara
N
N
D000818:Animals; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D006321:Heart / Q000502:physiology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors