Abstract
Angiogenesis is a fundamental vertebrate developmental process that requires signalling by the secreted protein vascular endothelial growth factor-A (VEGF-A). VEGF-A functions in the development of embryonic structures, during tissue remodelling and for the growth of tumour-induced vasculature. The study of the role of VEGF-A during normal development has been significantly complicated by the dominant, haplo-insufficient nature of VEGF-A-targeted mutations in mice. We have used morpholino-based targeted gene knock-down technology to generate a zebrafish VEGF-A morphant loss of function model. Zebrafish VEGF-A morphant embryos develop with an enlarged pericardium and with major blood vessel deficiencies. Morphological assessment at 2 days of development indicates a nearly complete absence of both axial and intersegmental vasculature, with no or reduced numbers of circulating red blood cells. Molecular analysis using the endothelial markers fli-1 and flk-1 at 1 day of development demonstrates a fundamental distinction between VEGF-A requirements for axial and intersegmental vascular structure specification. VEGF-A is not required for the initial establishment of axial vasculature patterning, whereas all development of intersegmental vasculature is dependent on VEGF-A signalling. The zebrafish thus serves as a quality model for the study of conserved vertebrate angiogenesis processes during embryonic development.
Highlights
Signalling by members of the vascular endothelial growth factor (VEGF) gene family is implicated in the formation of vasculature during embryogenesis, during wound healing and for the growth of tumour-induced vasculature
We show that the establishment of the axial and intersegmental vasculature has distinct requirements for vascular endothelial growth factor-A (VEGF-A) signalling, as revealed by analysis of the expression of two endothelial markers, the tyrosine kinase VEGF receptor, ̄k-1 (Sumoy et al, 1997; Fouquet et al, 1997; Thompson et al, 1998) and the early vascular marker, the transcription factori-1 (Thompson et al, 1998; Brown et al, 2000)
Zebra®sh VEGF-A is expressed during embryogenesis in the anterior nervous system, in mesodermanking the prospective heart ®elds, and in somitic mesoderm thatanks the developing endoderm (Liang et al, 1998)
Summary
Signalling by members of the vascular endothelial growth factor (VEGF) gene family is implicated in the formation of vasculature during embryogenesis, during wound healing and for the growth of tumour-induced vasculature (for reviews, see Carmeliet and Collen, 1997; Ferrara, 1999). Both axial and intersegmental vasculature fail to function in VEGF-A morphant embryos, indicating a role for VEGF-A beyond the establishment ofk-1 andi1 expression in blood vessel formation. Similar phenotypes were observed in some mutations found in chemical mutagenesis screens, suggesting a possible role for these genes in VEGF-A signalling in the zebra®sh embryo.
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