BAMBI Regulates Angiogenesis and Endothelial Homeostasis through Modulation of Alternative TGFβ Signaling

Abstract

BackgroundBAMBI is a type I TGFβ receptor antagonist, whose in vivo function remains unclear, as BAMBI− /− mice lack an obvious phenotype.Methodology/Principal FindingsIdentifying BAMBI’s functions requires identification of cell-specific expression of BAMBI. By immunohistology we found BAMBI expression restricted to endothelial cells and by electron microscopy BAMBI− /− mice showed prominent and swollen endothelial cells in myocardial and glomerular capillaries. In endothelial cells over-expression of BAMBI reduced, whereas knock-down enhanced capillary growth and migration in response to TGFβ. In vivo angiogenesis was enhanced in matrigel implants and in glomerular hypertrophy after unilateral nephrectomy in BAMBI− /− compared to BAMBI+/+ mice consistent with an endothelial phenotype for BAMBI− /− mice. BAMBI’s mechanism of action in endothelial cells was examined by canonical and alternative TGFβ signaling in HUVEC with over-expression or knock-down of BAMBI. BAMBI knockdown enhanced basal and TGFβ stimulated SMAD1/5 and ERK1/2 phosphorylation, while over-expression prevented both.Conclusions/SignificanceThus we provide a first description of a vascular phenotype for BAMBI− /− mice, and provide in vitro and in vivo evidence that BAMBI contributes to endothelial and vascular homeostasis. Further, we demonstrate that in endothelial cells BAMBI interferes with alternative TGFβ signaling, most likely through the ALK 1 receptor, which may explain the phenotype observed in BAMBI− /− mice. This newly described role for BAMBI in regulating endothelial function has potential implications for understanding and treating vascular disease and tumor neo-angiogenesis.

Vessel wall BAMBI contributes to hemostasis and thrombus stability

“…35,36 A recent study highlighted differences in the endothelial composition of the myocardium and glomeruli in Bambi 2/2 mice compared with wild-type animals. 37 An enhanced angiogenic response in vivo using Matrigel implants was also observed. 37 A role for BAMBI in some of the remodeling processes following heart pressure overload 38 and mechanical injury of the femoral artery has also been reported, 39 although how these phenotypes are conferred is still unclear.…”

“…37 An enhanced angiogenic response in vivo using Matrigel implants was also observed. 37 A role for BAMBI in some of the remodeling processes following heart pressure overload 38 and mechanical injury of the femoral artery has also been reported, 39 although how these phenotypes are conferred is still unclear.…”

“…7 BAMBI is highly expressed in platelets 6,7 and ECs. 17,37 Lack of thrombus stability observed in Bambi-deficient mice could be due to a lack of BAMBI in one or both of these cell types. To address this, laser-induced thrombus formation was examined in radiation chimeric mice generated through bone marrow transplantation.…”

“…Collectively, our results suggested that BAMBI deficiency did not lead to a platelet or plasma coagulation defect that could be responsible for the in vivo phenotype observed in thrombosis models. As BAMBI was found to be highly expressed in ECs and in platelets, 6,7,17,37 we generated radiation chimeric mice to evaluate the contribution of endothelium BAMBI in thrombus formation. Figure 3).…”

Downregulation of HOPX Controls Metastatic Behavior in Sarcoma Cells and Identifies Genes Associated with Metastasis

“…We subsequently validated the microarray results by qRT-PCR of several genes, ADCY7, ARGHDIB, BAMBI, FOXG1, FSCN1, FUCA1, GFPT2, ITPR3, ITGA4, LSP1, NCAM1, NUDT14, RGS20, RHOF, and RIAM, that have already been implicated in cell migration, adhesion, or angiogenesis (28,(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46). The results from qRT-PCR analysis (Fig.…”