VEGF-PLCγ1 pathway controls cardiac contractility in the embryonic heart
VEGF-PLCγ1 pathway controls cardiac contractility in the embryonic heart
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DOI：
10.1101/gad.1319405
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发表时间：
2005-07-01
影响因子：
10.5
通讯作者：
Fishman, MC
中科院分区：
文献类型：
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作者：
Rottbauer, W;Just, S;Fishman, MC
心脏跳动的强度可以在几秒钟内适应血压或血流的变化。这种动态平衡适应的机制尚不清楚。我们在带有无节拍突变的斑马鱼胚胎的心脏中寻找收缩能力差的原因。我们通过克隆发现，这是由于磷脂酶C-伽马1(plc-伽马1)基因突变所致。在突变胚胎中，通过选择性地针对心肌细胞表达PLC-Gamma-1可以恢复收缩功能。在其他情况下，已知PLC Gamma 1可以传递血管内皮细胞生长因子(VEGF)的信号，我们在这里表明，取消VEGF也会干扰心肌收缩能力。有些出乎意料的是，Flt-1是负责的血管内皮生长因子受体。我们证明了同样的系统在大鼠身上也发挥了作用。阻断VEGF-PLC-Gamma 1信号通路可减少大鼠心肌细胞的钙瞬变，而血管内皮生长因子通过增加钙瞬变而对心肌细胞产生正性变力作用。因此，心脏肌肉使用血管内皮生长因子-PLC伽马1级联来控制心跳的强度。我们推测，这种旁分泌系统可能有助于心脏收缩能力的正常和病理调节。
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 gamma 1 (plc gamma 1) gene. In mutant embryos, contractile function can be restored by PLC gamma 1 expression directed selectively to cardiac myocytes. In other situations, PLC gamma 1 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-PLC gamma 1 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-PLC gamma 1 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.