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

Abstract

Lymphatic vessels (LVs) play critical roles in the maintenance of fluid homeostasis and in pathological conditions, including cancer metastasis. Although mutations in ALK1, a member of the transforming growth factor (TGF)-β/bone morphogenetic protein (BMP) receptor family, have been linked to hereditary hemorrhagic telangiectasia, a human vascular disease, the roles of activin receptor-like kinase 1 (ALK-1) signals in LV formation largely remain to be elucidated. We show that ALK-1 signals inhibit LV formation, and LVs were enlarged in multiple organs in Alk1-depleted mice. These inhibitory effects of ALK-1 signaling were mediated by BMP-9, which decreased the number of cultured lymphatic endothelial cells. Bmp9-deficient mouse embryos consistently exhibited enlarged dermal LVs. BMP-9 also inhibited LV formation during inflammation and tumorigenesis. BMP-9 downregulated the expression of the transcription factor prospero-related homeobox 1, which is necessary to maintain lymphatic endothelial cell identity. Furthermore, silencing prospero-related homeobox 1 expression inhibited lymphatic endothelial cell proliferation. Our findings reveal a unique molecular basis for the physiological and pathological roles of BMP-9/ALK-1 signals in LV formation.lymphangiogenesis | angiogenesis | blood vascular endothelial cells

Development of the lymphatic system: new questions and paradigms

“…The role of the BMP signaling pathway during lymphatic formation has also been analyzed in mice. In line with the Bmp2b-associated phenotypes observed in zebrafish, Bmp9 was shown to negatively regulate lymphatic formation in mammals (Levet et al, 2013;Yoshimatsu et al, 2013). Bmp9 KO results in dilation of the dermal lymphatics at E15.5, suggesting enhanced proliferation of LECs (Yoshimatsu et al, 2013).…”

“…In line with the Bmp2b-associated phenotypes observed in zebrafish, Bmp9 was shown to negatively regulate lymphatic formation in mammals (Levet et al, 2013;Yoshimatsu et al, 2013). Bmp9 KO results in dilation of the dermal lymphatics at E15.5, suggesting enhanced proliferation of LECs (Yoshimatsu et al, 2013). In addition, Bmp9 KO neonates show increased numbers of LECs in the mesentery, causing enlargement of collecting lymphatic vessels (Levet et al, 2013).…”

“…Members of the BMP family act as repressors of lymphatic formation in vivo (Dunworth et al, 2014;Levet et al, 2013;Yoshimatsu et al, 2013). In zebrafish, Bmp2b upregulation at 25-26 hpf induces ectopic venous sprouting, whereas forced expression of Noggin 3, which is an endogenous inhibitor of BMP signaling, results in impaired caudal vein plexus formation (Wiley et al, 2011).…”

BMP-9 balances endothelial cell fate

“…1). Yoshimatsu et al (5) highlight the role of a ligandreceptor system that represses LEC differentiation, proliferation, and lymphangiogenesis. The receptor ALK-1, previously implicated in arteriovenous specification (6), is activated by the TGF-β-related ligand bone morphogenetic protein-9 (BMP-9) and inhibits the switch from BEC to LEC differentiation by repressing the latter and promoting the former.…”

P7170: A Novel Molecule with Unique Profile of mTORC1/C2 and Activin Receptor-like Kinase 1 Inhibition Leading to Antitumor and Antiangiogenic Activity

“…Hu-Lowe and colleagues have demonstrated using ALK1 À/À mice and zebrafish harboring a loss-of-function mutation that ALK1 plays a fundamental role in vasculogenesis, particularly in vessel maturation and in the organization of neo-angiogenic vessels (19,38). In addition, overexpression of ALK1 has been observed in a wide variety of tumor blood vessels, including lymphomas, prostate, skin, thyroid, kidney, ovarian, lung, pancreatic, and liver cancers (39,40). Notably, recent development of two agents targeting ALK1; an antibody developed by Pfizer, PF-03446962 (Clinical Trial Identifier: NCT01911273; ref.…”