VEGF–PLCγ1 pathway controls cardiac contractility in the embryonic heart

Abstract

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 ␥1 (plc␥1) gene. In mutant embryos, contractile function can be restored by PLC␥1 expression directed selectively to cardiac myocytes. In other situations, PLC␥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␥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␥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.[Keywords: VEGF; PLC␥1; contractility; heart; zebrafish] Supplemental material is available at http://www.genesdev.org.

HBEGF, SRA1, and IK: Three cosegregating genes as determinants of cardiomyopathy

“…3; Supplemental Table 5B; Supplemental Movies 1-8). As observed in other zebrafish heart failure mutants (Rottbauer et al 2005), MOhbegf, MO-sra1, and MO-ik injected embryos also display a pericardial edema at 72 hpf.…”

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“…0183), which conform to EU Directive 2010/63/EU. Care and breeding of zebrafish, Danio rerio, was conducted as described previously [6]. The following mutant alleles were used: flatline smyd1b zf340/zf340 [3] and steif unc45b sb60/sb60 [1].…”

“…For the spontaneous movement assay false-colored superimposed overviews of 24 hpf embryos were analyzed. Whole-mount RNA in situ hybridization was carried out essentially as described previously [6] using a full-length smyd1b antisense probe, as well as antisense probes for zebrafish smyd1a, vmhc, amhc, hsp90aa1 and unc45b. Whole mount fluorescent immunostainings were carried out as described in Inoue and Wittbrodt [9].…”

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“…Analysis of contractility mutants also suggests that endocardial-myocardial signaling may be required to maintain contractility. Mutation of dead beat causes a progressive loss of ventricular contractility; this locus encodes PLCγ1, a component of the vascular endothelial growth factor (VEGF) signaling pathway [53]. Mosaic analyses demonstrate that dead beat is required cell-autonomously for maintenance of ventricular contractility, thereby demonstrating a previously unappreciated role for VEGF signaling in cardiomyocytes.…”

“…Mosaic analyses demonstrate that dead beat is required cell-autonomously for maintenance of ventricular contractility, thereby demonstrating a previously unappreciated role for VEGF signaling in cardiomyocytes. Manipulation of VEGF-PLCγ1 signaling in rat cardiomyocytes in culture affects their calcium cycling, suggesting a similar function for VEGF in the embryonic heart [53].…”