Abstract
BackgroundThe signaling cascades that direct the morphological differentiation of the vascular system during early embryogenesis are not well defined. Several signaling pathways, including Notch and VEGF signaling, are critical for the formation of the vasculature in the mouse. To further understand the role of Notch signaling during endothelial differentiation and the genes regulated by this pathway, both loss-of-function and gain-of-function approaches were analyzed in vivo.ResultsConditional transgenic models were used to expand and ablate Notch signaling in the early embryonic endothelium. Embryos with activated Notch1 signaling in the vasculature displayed a variety of defects, and died soon after E10.5. Most notably, the extraembryonic vasculature of the yolk sac displayed remodeling differentiation defects, with greatly enlarged lumens. These phenotypes were distinct from endothelial loss-of-function of RBPJ, a transcriptional regulator of Notch activity. Gene expression analysis of RNA isolated from the yolk sac endothelia of transgenic embryos indicated aberrant expression in a variety of genes in these models. In particular, a variety of secreted factors, including VEGF and TGF-β family members, displayed coordinate expression defects in the loss-of-function and gain-of-function models.ConclusionsMorphological analyses of the in vivo models confirm and expand the understanding of Notch signaling in directing endothelial development, specifically in the regulation of vessel diameter in the intra- and extraembryonic vasculature. Expression analysis of these in vivo models suggests that the vascular differentiation defects may be due to the regulation of key genes through the Notch-RBPJ signaling axis. A number of these genes regulated by Notch signaling encode secreted factors, suggesting that Notch signaling may mediate remodeling and vessel diameter in the extraembryonic yolk sac via autocrine and paracrine cell communication. We propose a role for Notch signaling in elaborating the microenvironment of the nascent arteriole, suggesting novel regulatory connections between Notch signaling and other signaling pathways during endothelial differentiation.
Highlights
The signaling cascades that direct the morphological differentiation of the vascular system during early embryogenesis are not well defined
To activate and expand Notch1 signaling in the endothelia, a transgenic line RosaNotch [21] was used, which harbors a NOTCH 1 intracellular domain (N1ICD) cDNA downstream of a floxed STOP fragment targeted to the Rosa26 locus
To delete Notch signaling in the early endothelia, a mouse line was used which harbors a conditional allele of Rbpj (Rbpjf mice) [22]
Summary
The signaling cascades that direct the morphological differentiation of the vascular system during early embryogenesis are not well defined. The simple plexus of the yolk sac is remodeled and refined after E8.5 to form the larger diameter vessels During this process, extensive movements of endothelial cells within the plexus occur through a process termed intussusceptive arborization [3], reallocating cells from the capillaries to larger vessels, to assemble a more complex vasculature network [4,5]. Extensive movements of endothelial cells within the plexus occur through a process termed intussusceptive arborization [3], reallocating cells from the capillaries to larger vessels, to assemble a more complex vasculature network [4,5] This process forms the vitelline arteriole and venule, which participate in the contiguous blood flow with the embryonic vasculature, concomitant with the initiation of flow after E9.0. More work needs to be done to define the shared and distinct regulatory paths that control vascular differentiation in the various sites of development and in the adult
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