A XXXX Variant Inhibits Tumor Angiogenesis In Vitro and In Vivo through Direct Modulation of Endothelial Cell Biology.

@entity7 @entity5 @entity12017 @entity540 @entity319 @entity463 @entity1594 @entity7167
Bone morphogenetic proteins (BMPs), members of the TGF-b superfamily, have numerous biological activities including control of growth, differentiation, and vascular development. Using an in vitro co-culture endothelial cord formation assay, we investigated the role of a @entity12017 variant (BMP7v) in @entity7 , @entity540 , and @entity5 -driven angiogenesis. BMP7v treatment led to disruption of neo-endothelial cord formation and regression of existing @entity7 and @entity540 cords in vitro. Using a series of @entity5 cell models capable of driving angiogenesis in vitro, BMP7v treatment completely blocked cord formation. Pre-treatment of endothelial cells with BMP7v significantly reduced their cord forming ability, indicating a direct effect on endothelial cell function. BMP7v activated the canonical SMAD signaling pathway in endothelial cells but targeted gene knockdown using shRNA directed against @entity1594 suggests this pathway is not required to mediate the anti-angiogenic effect. In contrast to SMAD activation, BMP7v selectively decreased ERK and AKT activation, significantly decreased endothelial cell migration and down-regulated expression of critical RTKs involved in @entity7 and FGF angiogenic signaling, @entity319 and @entity7167 respectively. Importantly, in an in vivo angiogenic plug assay that serves as a measurement of angiogenesis, BMP7v significantly decreased hemoglobin content indicating inhibition of neoangiogenesis. In addition, BMP7v significantly decreased angiogenesis in @entity463 stem-like cell (GSLC) Matrigel plugs and significantly impaired in vivo growth of a GSLC xenograft with a concomitant reduction in microvessel density. These data support BMP7v as a potent anti-angiogenic molecule that is effective in the context of @entity5 angiogenesis.
