Venous-derived angioblasts generate organ-specific vessels during embryonic development

Abstract

Formation and remodeling of vascular beds are complex processes orchestrated by multiple signaling pathways. Although it is well accepted that vessels of a particular organ display specific features that enable them to fulfill distinct functions, the embryonic origins of tissue-specific vessels and the molecular mechanisms regulating their formation are poorly understood. The subintestinal plexus of the zebrafish embryo comprises vessels that vascularize the gut, liver and pancreas and, as such, represents an ideal model in which to investigate the early steps of organ-specific vessel formation. Here, we show that both arterial and venous components of the subintestinal plexus originate from a pool of specialized angioblasts residing in the floor of the posterior cardinal vein (PCV). Using live imaging of zebrafish embryos, in combination with photoconvertable transgenic reporters, we demonstrate that these angioblasts undergo two phases of migration and differentiation. Initially, a subintestinal vein forms and expands ventrally through a Bone Morphogenetic Protein-dependent step of collective migration. Concomitantly, a Vascular Endothelial Growth Factor-dependent shift in the directionality of migration, coupled to the upregulation of arterial markers, is observed, which culminates with the generation of the supraintestinal artery. Together, our results establish the zebrafish subintestinal plexus as an advantageous model for the study of organ-specific vessel development and provide new insights into the molecular mechanisms controlling its formation. More broadly, our findings suggest that PCV-specialized angioblasts contribute not only to the formation of the early trunk vasculature, but also to the establishment of late-forming, tissue-specific vascular beds.

Vegfa signaling promotes zebrafish intestinal vasculature development through endothelial cell migration from the posterior cardinal vein

“…In agreement with our results, time-lapse imaging and fate mapping using Kaede photoconversion confirmed that both SIV and SIA are derived from the PCV. Differently from Hen et al which reported that the SIA is derived from the SIV progenitor vessel (Hen et al, 2015), we find that the angioblasts from the PCV directly populate the SIA and SIV, and the SIA is already present when the interconnecting vessels (ICV) form. The SIA is located deep and very close to the PCV, therefore it is difficult to observe the early SIA progenitors using same promoter lines (fli1:dsRed; fli1:nGFP) which show uniform expression in the PCV and intestinal vasculature.…”

“…While this manuscript was in preparation, several other groups also reported the description of intestinal vessel development (Goi and Childs, 2015; Hen et al, 2015; Lenard et al, 2015; Nicenboim et al, 2015). In agreement with our results, time-lapse imaging and fate mapping using Kaede photoconversion confirmed that both SIV and SIA are derived from the PCV.…”

Cell behaviors and dynamics during angiogenesis

“…Other zebrafish vascular beds that have attracted attention (Fig. 1) include the vasculature of the head and the brain (Gore et al, 2012;Isogai et al, 2001;Kimura et al, 2015;Lenard et al, 2013;Chen et al, 2012), the caudal vein plexus (Wiley et al, 2011) and the subintestinal veins (SIVs) (Goi and Childs, 2016;Hen et al, 2015;Koenig et al, 2016;Lenard et al, 2015;Nicoli et al, 2007). It should be noted, however, that ECs in different vascular beds might use different molecular cues and morphogenetic mechanisms to form vascular tubes.…”

Development of the lymphatic system: new questions and paradigms

“…Moreover, all of these cells co-expressed the well-established angioblast marker kdrl, leaving open the possibility of alternative, non-venous origins for these lymphangioblasts. In addition, recent studies uncovered a novel pool of specialized angioblasts in the floor of the CV at 22-24 hpf that gives rise to PACs as well as to arterial and venous ECs (Hen et al, 2015;Nicenboim et al, 2015). These angioblasts were shown to be molecularly distinct from surrounding venous cells, displaying enriched expression of angioblast and arterial markers, and to arise directly from a restricted angioblast population located in the lateral plate mesoderm.…”