Vascularization of the mouse embryo: A study of flk‐1, tek, tie, and vascular endothelial growth factor expression during development

Abstract

We report the detailed developmental expression profiles of three endothelial specific receptor tyrosine kinases (RTKs) flk-1, tek, tie, as well as vascular endothelial growth factor (VEGF), the flk-1 ligand. We also examined the expression of the other VEGF receptor, flt-1, during placental development. flk-1, tek, and tie transcripts were detected sequentially at one-half day intervals starting at E7.0, suggesting that each of these RTKs play a unique role during vascularization of the mouse embryo. All three RTKs were expressed in the extraembryonic and embryonic mesoderm in regions that eventually give rise to the vasculature. Except for the expression of tek and flk-1 in the mesoderm of the amnion, the expression of these RTKs from E8.5 onwards was virtually indistinguishable. An abundant amount of flt-1 transcripts was found in the spongiotrophoblast cells of the developing placenta from E8.0 onwards. This cellular compartment is located between the maternal and labyrinthine layers of the placenta, which both express VEGF. VEGF transcripts were detected as early as E7.0 in the endoderm juxtaposed to the flk-1 positive mesoderm, and later in development VEGF expression displayed an expression profile both contiguous with that of flk-1, and also in tissues found some distance from the flk-1-expressing endothelium. These results suggest a possible dual role for VEGF which includes a chemotactic and/or a cellular maintenance role for VEGF during vascularization of the mouse embryo. o 1995 Wiley-Liss, Inc.

Neovascularization of the Xenopus embryo

“…Complementary domains of expression for flk-1 and VEGF have been reported for a number of embryonic tissues in mouse and quail (Dumont et al, 1995;Flamme et al, 1995a). In general, flk-1 and VEGF expression is also observed in juxtaposed tissues in the Xenopus embryo, with flk-1 being restricted to cells of mesodermal origin and VEGF in adjacent endodermal or neural tissues (Fig.…”

“…In mouse and quail embryos, flk-1 is expressed in a pattern approximately complementary to that of VEGF (Dumont et al, 1995;Flamme et al, 1995a), strongly implying a role for this receptor-ligand pair in neovascularization of the embryo. flk-1 expression is a very early marker for vascular endothelium, being expressed before flt-1 or other endothelial specific receptor tyrosine kinases such as tie-2 and tek (Dumont et al, 1992;Schnü rch and Risau, 1993;Iwama et al, 1993).…”

“…4F). Based on observations of mouse vascular development, it has been suggested that VEGF may exhibit chemotactic effects on flk-1 expressing cells (Dumont et al, 1995) and it is possible that VEGF expressed by the hypochord plays a similar role during dorsal aorta development in Xenopus. Recent work in zebrafish (Fouquet et al, 1997) demonstrates that mutant embryos which lack a notochord fail to develop a dorsal aorta and that dorsal aorta formation may therefore depend on signals from the notochord.…”

“…One particular growth factor, VEGF, is considered to be especially important for vascular development because of its potent vasculogenic activity, both in vitro and in vivo (Keck et al, 1989;Leung et al, 1989;Wilting et al, 1996), and because it is consistently expressed at high levels in close proximity to the developing endothelium of the early quail and mouse embryos (Breier et al, 1992;Dumont et al, 1995;Flamme et al, 1995a). Alternative splicing generates three forms of VEGF in mouse (mVEGF120, 164, and 188;Ferrara et al, 1992).…”

The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R

“…They play a crucial role in the development of the embryonic cardiovascular system, and they are also involved in angiogenesis in normal physiological and pathological processes. These RTKs are expressed in di erent spatial and temporal patterns during development (Dumont et al, 1995), suggesting that they play distinct roles within the endothelial cell lineage. This subgroup of RTKs has been placed into two subfamilies according to similarities in their primary amino acid sequences (Dumont et al, 1993;Mustonen and Alitalo, 1995).…”