BMP9 and BMP10 are critical for postnatal retinal vascular remodeling

Abstract

ALK1 is a type I receptor of the TGF-β family that is involved in angiogenesis. Circulating BMP9 was identified as a specific ligand for ALK1 inducing vascular quiescence. In this work, we found that blocking BMP9 with a neutralizing antibody in newborn mice significantly increased retinal vascular density. Surprisingly, Bmp9-KO mice did not show any defect in retinal vascularization. However, injection of the extracellular domain of ALK1 impaired retinal vascularization in Bmp9-KO mice, implicating another ligand for ALK1. Interestingly, we detected a high level of circulating BMP10 in WT and Bmp9-KO pups. Further, we found that injection of a neutralizing anti-BMP10 antibody to Bmp9-KO pups reduced retinal vascular expansion and increased vascular density, whereas injection of this antibody to WT pups did not affect the retinal vasculature. These data suggested that BMP9 and BMP10 are important in postnatal vascular remodeling of the retina and that BMP10 can substitute for BMP9. In vitro stimulation of endothelial cells by BMP9 and BMP10 increased the expression of genes involved in the Notch signaling pathway (Jagged1, Dll4, Hey1, Hey2, Hes1) and decreased apelin expression, suggesting a possible cross-talk between these pathways and the BMP pathway.

BMP9 and BMP10 are necessary for proper closure of the ductus arteriosus

“…We also found that BMP9 and BMP10 strongly induced the mRNA expression of several transcription factors (SNAI1, SNAI2, ZEB2, TWIST1, and FOXC2) known to be important in the initiation of EMT or endMT (14). In accordance, it has already been described that BMP9 and BMP10 transiently induce the expression of HEY1, HEY2, and HES1 (8,24), which are transcription factors of the Notch signaling pathway also known to be involved in EMT (14). Taken together, these data allow us to propose that, in Bmp9-KO pups injected with anti-BMP10 antibody (P1 and P3), ECs fail to go through a transition into a mesenchymal-like phenotype, and this defect of remodeling leads to loose cell interactions that will result in the reopening of the DA.…”

“…In 2007, it was demonstrated that BMP9 and BMP10 bind with high affinity to the endothelial-specific receptor activin receptor-like kinase 1 (ALK1), a type 1 receptor of the TGFβ family (6) whose mutations are involved in vascular diseases (5). Both BMP9 and BMP10 are present in blood, and their circulating levels are particularly elevated in mice around birth (7,8), suggesting that they could play a role in pre-and postnatal development. In the present work, we addressed whether BMP9 and BMP10 could be involved in DA closure.…”

Bone morphogenetic protein-9 inhibits lymphatic vessel formation via activin receptor-like kinase 1 during development and cancer progression

“…1) may have been caused by differences in the method used to inhibit ALK-1 signaling. Furthermore, this variance may also have been caused by the contribution of BMP-10, which is another physiological ligand of ALK-1 (29). Although Bmp10-deficient mice exhibit severe defects in cardiac tissues, no phenotypes in vascular systems have been described in Bmp10-deficient mice (27), suggesting that the physiological roles of BMP-10 may be limited to the cardiac development.…”

“…Several lines of evidence have suggested that BMP-9 and BMP-10 are the physiological ligands for ALK-1 (27)(28)(29). To examine whether the loss of Bmp9 expression exhibits phenotypes similar to those observed in Alk1-depleted mice, we analyzed the structure of LVs in Bmp9 KO mice.…”

“…To examine whether the loss of Bmp9 expression exhibits phenotypes similar to those observed in Alk1-depleted mice, we analyzed the structure of LVs in Bmp9 KO mice. Bmp9 KO mice were viable and fertile without gross abnormalities (29). We investigated the embryonic phenotypes in dermal lymphatics by performing whole-mount fluorescence immunostaining of embryonic back skin, using an antibody to VEGFR3.…”