VEGF-PLCgamma1 pathway controls cardiac contractility in the embryonic heart.
The strength of the heart beat can accommodate in seconds to changes in blood pressure or flow. The mechanism for such homeostatic adaptation is unknown. We sought the cause of poor contractility in the heart of the embryonic zebrafish with the mutation dead beat. We find through cloning that this is due to a mutation in the phospholipase C gamma1 (plcgamma1) gene. In mutant embryos, contractile function can be restored by PLCgamma1 expression directed selectively to cardiac myocytes. In other situations, PLCgamma1 is known to transduce the signal from vascular endothelial growth factor (VEGF), and we show here that abrogation of VEGF also interferes with cardiac contractility. Somewhat unexpectedly, FLT-1 is the responsible VEGF receptor. We show that the same system functions in the rat. Blockage of VEGF-PLCgamma1 signaling decreases calcium transients in rat ventricular cardiomyocytes, whereas VEGF imposes a positive inotropic effect on cardiomyocytes by increasing calcium transients. Thus, the muscle of the heart uses the VEGF-PLCgamma1 cascade to control the strength of the heart beat. We speculate that this paracrine system may contribute to normal and pathological regulation of cardiac contractility.
Rottbauer
Wolfgang
W
Department of Medicine III, University of Heidelberg, D-69120 Heidelberg, Germany. wolfgang.rottbauer@med.uni-heidelberg.de
Just
Steffen
S
Wessels
Georgia
G
Trano
Nicole
N
Most
Patrick
P
Katus
Hugo A
HA
Fishman
Mark C
MC
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D006321:Heart / Q000196:embryology* / Q000502:physiology; D009200:Myocardial Contraction / Q000502:physiology*; D051966:Phospholipase C gamma; D051381:Rats; D010738:Type C Phospholipases / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology*
D017931:DNA Primers; D042461:Vascular Endothelial Growth Factor A; D010738:Type C Phospholipases; D051966:Phospholipase C gamma