Bone Morphogenetic Protein functions as a context-dependent angiogenic cue in vertebrates

Abstract

Bone Morphogenetic Protein (BMP) signaling has been implicated in diverse biological processes. Although how BMP signaling regulates behaviors of endothelial cells during angiogenesis are not fully understood, increasing evidence indicate functions of BMP signaling components are essential in developmental and pathological angiogenesis. Here we review recent advances in delineating the functions of BMP signaling during angiogenesis. In addition, we discuss downstream pathways that transduce BMP signaling in endothelial cells, and factors that modulate BMP signaling response in endothelial cells. Finally, we provide recent insight on how BMP signaling functions as a context dependent angiogenic cue.

Fig. 1. Methods of regulating BMP responsiveness

Extracellular antagonists bind to BMP ligands and prevent the ligands from interacting with receptors. BMP9 BMP10 bind to non-angiogenic heteromeric receptor complexes consisting of BMPRII and ALK1, which may limit the availability of angiogenic ligand-receptor complexes. In contrast, when angiogenic ligand-receptor complexes are formed, and inhibitory BMP ligands are absent, co-SMAD is translocated into the nucleus and promotes the transcription of BMP target genes within endothelial cells. Alternative signaling pathways may also have important roles in regulating the intracelluar responses to BMP stimulus.

Figure 2

VEGFA and BMP pathways have distinct as well as overlapping intracellular targets. The VEGFA pathway is known to phosphorylate and activate, among other factors, MAPK signaling cascades, which includes both p38 and ERK. Canonical BMP signaling activates Smads however BMP stimulation has been shown to effectively activate MAPK signaling cascades as well. During angiogenesis, BMP requires activation of ERK and not p38 [47].

Figure 3

Bmp signaling is necessary and sufficient for sprouting from the axial vein. Blood vessels in wild-type (A, B), Tg(hsp70:noggin3) (C, D) and Tg(hsp70:bmp2b) (E, F) embryos in the Tg(kdrl:GFP) transgenic background (A, C, E). The entire vascular network of 42hpf embryos was analyzed using epiflourescent images; dashed boxes represent the trunk and tail areas analyzed below. Z-stacks from the trunk and tail regions were used to make 3-D color projections (A, C, and E), Filopodia formation of Tg(fli1:nGFP);Tg(kdrl:ras-mCherry) embryos starting at 32hpf (B, D, and F). Arrows in panel c and d show sprouts from the axial vein that fail to make connections in Tg(hsp70:noggin3) embryos. Arrowheads in panel e and f point to ectopic sprouts that branch from the axial vein in Tg(hsp70:bmp2b) embryos. Abbreviations: DA, dorsal aorta; VV, ventral vein; DV, dorsal vein; NC, notocord; NT, neural tube; ISA, intersegmental artery.

Figure 4

Distinct angiogenic cues regulate arterial and venous angiogenesis during early zebrafish development. VEGFA regulates sprouting from the Dorsal Aorta, while BMP signaling is the predominate angiogenic cue during venous angiogenesis off the Axial Vein. VEGFA expressed dorsally within somites attracts sprouts from the Dorsal Aorta. Meanwhile, ventral expression of BMP regulates sprouting from the axial vein.