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Biochem Biophys Res Commun
2007 Aug 03;3593:431-7. doi: 10.1016/j.bbrc.2007.05.140.
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Constitutive over-expression of VEGF results in reduced expression of Hand-1 during cardiac development in Xenopus.
Nagao K
,
Taniyama Y
,
Koibuchi N
,
Morishita R
.
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During heart development, various signaling cascades are tightly regulated in a stage- and region-dependent manner. Vascular endothelial growth factor (VEGF) is one of the important molecules required for both vascular development and cardiac morphogenesis. VEGF receptors are present in the embryonic heart, so we focused on heart formation in VEGF-over-expressing Xenopus embryos. Over-expression of VEGF(170) caused disorganized vessels, while the expression of an endothelial marker, Tie-2, was increased. The embryo's heart was distinctly larger than that of control, and showed abnormal morphology. Histological analysis of these embryos showed failure of heart looping. In situ hybridization with Hand-1, which controls intrinsic morphogenetic pathways, revealed that the expression level of Hand-1 was decreased in the heart region. These results suggest that increased VEGF(170) levels disturb Hand-1 expression in the region required for normal heart morphogenesis. VEGF expression level may be important in heart morphology during embryonic development.
Fig. 1.
Temporal and spatial VEGF expression pattern in Xenopus embryonal development. (A) Expression of VEGF assayed by RT-PCR of total RNA prepared from the indicated developmental stages. As a control, the same samples were assayed for ODC mRNA expression. In VEGF variants, both VEGF120 and VEGF190 were seen at yolk plug stage 11. (B) VEGF mRNA distribution was analyzed by whole-mount in situ hybridization in wild-type Xenopus embryos at stage 24, 27, 31, and 33/34. Effects of VEGF170 on vascular development. (C) In situ hybridization detection of angiogenesis and hematopoiesis using Tie-2 (blue) and α-globin (brown) probes at stage 32. Control embryos (a and b), embryos injected with VEGF170 (c and d) or VEGF morpholino (e and f). Lateral view of embryos (a, c, and e). Ventral view of embryos (b, d, and f) (B).
Fig. 2.
Effects of VEGF170 on cardiac development. (A) In situ hybridization with a myocardial-specific differentiation marker, TnIc. Control embryos (a), embryos injected with VEGF170 (b) or VEGF morpholino (c). (B) Score of embryos with the enlargement of the region of TnIc expression. The proportion of embryos with an enlargement heart was increased by VEGF170 mRNA injection compared with control.
Fig. 3.
Over-expression of VEGF170 inhibited the formation of heart looping. In situ hybridization to detect cardiac troponin transcripts (purple color) was completed before sectioning, and morphology was studied using eosin staining. Lateral view of embryos (aâc). Histological analysis of heart morphology in transverse sections of Xenopus embryos (dâh). Control embryos (a, d, and g) and embryos injected with VEGF170 (b, e, and h) showing severe edema (c and f). Transverse section demonstrating that heart tube looping did not form in VEGF170-injected embryos. Anterior section (d, e, and f) and posterior section (g and h) of the heart tube (green allow head shows the position of heart bending).
Fig. 4.
Expression of heart markers in VEGF170-injected embryos. (c, d, g, h, l, and m) Stage 35 control embryos. (a, b, e, f, j, and k) Stage 35 embryos injected with 1000 pg VEGF170 mRNA in the one vegetal dorsal region at the eight-cell stage. (aâd) Tbx5 expression. (eâh) Hand-2 expression. (jâm) Hand-1 expression. Note the absence of Hand-1 expression in the heart in VEGF170-injected embryos (red arrowhead in panels k and m).
