Diversity is in my veins: role of bone morphogenetic protein signaling during venous morphogenesis in zebrafish illustrates the heterogeneity within endothelial cells - PubMed (original) (raw)
Review
Diversity is in my veins: role of bone morphogenetic protein signaling during venous morphogenesis in zebrafish illustrates the heterogeneity within endothelial cells
Jun-Dae Kim et al. Arterioscler Thromb Vasc Biol. 2014 Sep.
Abstract
Endothelial cells are a highly diverse group of cells which display distinct cellular responses to exogenous stimuli. Although the aptly named vascular endothelial growth factor-A signaling pathway is hailed as the most important signaling input for endothelial cells, additional factors also participate in regulating diverse aspects of endothelial behaviors and functions. Given this heterogeneity, these additional factors seem to play a critical role in creating a custom-tailored environment to regulate behaviors and functions of distinct subgroups of endothelial cells. For instance, molecular cues that modulate morphogenesis of arterial vascular beds can be distinct from those that govern morphogenesis of venous vascular beds. Recently, we have found that bone morphogenetic protein signaling selectively promotes angiogenesis from venous vascular beds without eliciting similar responses from arterial vascular beds in zebrafish, indicating that bone morphogenetic protein signaling functions as a context-dependent regulator during vascular morphogenesis. In this review, we will provide an overview of the molecular mechanisms that underlie proangiogenic effects of bone morphogenetic protein signaling on venous vascular beds in the context of endothelial heterogeneity and suggest a more comprehensive picture of the molecular mechanisms of vascular morphogenesis during development.
Keywords: bone morphogenetic protein receptors; vascular endothelial cells; veins; zebrafish.
© 2014 American Heart Association, Inc.
Figures
Figure 1. Differentiation and morphogenesis of endothelial cells
(A) The lateral plate mesoderm contains endothelial progenitors which give rise to either arterial or venous endothelial cells. While differentiation of arterial endothelial cells is regulated by Hedgehog and VEGF-A signaling, the signaling pathways that regulate differentiation of venous endothelial cells is currently unknown. BMP signaling is a candidate for such a signaling input. (B) Once specified, arterial and venous endothelial cells segregate from arterial and venous vascular beds. Sprouting angiogenesis within arteries is regulated by Dll4 and Notch interaction. Within the nucleus, active Notch signaling triggers transcription of target genes (1). A subset of BMP ligands, notably BMP9, intersects with Notch/Dll4 signaling to induce a distinct group of target genes (3), in addition to initiating the transcription of their own target genes (2). Abbreviations: EPC: Endothelial Progenitor Cells, AEC: Arterial Endothelial Cells, VEC: Venous Endothelial Cells, T: Tip Cell, S: Stalk Cell.
Figure 2. Diverse effects of BMP signaling in endothelial cells
BMP ligands function as dimers, and their gradient is regulated by extracellular antagonists. The ligands bind to heterotetrameric receptor complexes whose function is modulated by Type III receptors. Activated BMP receptors can elicit diverse cellular responses including cytoskeletal rearrangement and initiation of target gene transcription via SMAD1/5/8 and MAPKs. Within the signaling receiving cells, the amplitude of the BMP signaling response can be modulated by additional factors such as SMAD6 and PRMT1.
Figure 3. Distinct function of VEGF-A and BMP signaling in zebrafish endothelial cells
In zebrafish, Vegf-A and Bmp2b, an ortholog of mammalian BMP2, induce angiogenic responses from a distinct subpopulation of endothelial cells. Stimulation of Vegf-A can only increase arterial branching from the dorsal aorta, but fails to induce venous branching from the cardinal vein. Conversely, Bmp2b signaling can only elicit an angiogenic response in venous endothelial cells.
Figure 4. Heterogeneity within endothelial cells modulate responses to BMP signaling
(A) Trunk region of 26hpf Tg(BRE:EGFP);Tg(kdrl:mCherry) transgenic zebrafish embryos show the highly heterogeneous nature of endothelial cells. Panels show merged image (top), Tg(kdrl:mCherry) expression (middle), and Tg(BRE:EGFP) expression. Endothelial cells with active BMP signaling appear to preferentially localize to the tip cell position within venous angiogenic sprouts (white arrows), while those with inactive BMP signaling (asterisks) assume the stalk cell position within venous angiogenic sprouts, hinting the link between high BMP signaling activity and venous tip cell in this specific vascular bed. (B) Schematic illustration of sprouting angiogenesis in arterial and venous endothelial cells. In arterial endothelial cells, the VEGF-A gradient functions as the key factor to specify tip cells (T) and stalk cells (S). BMP signaling may exert a similar function in venous endothelial cells.
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