Host: The Japanese Society of Toxicology
Formation and maintenance of blood and lymphatic vessels are regulated by various cytokines including bone morphogenetic proteins (BMPs) that are members of transforming growth factor (TGF)-β family. 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 TGF-β/ 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 Prox1, which is necessary to maintain lymphatic endothelial cell identity. Furthermore, silencing Prox1 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. In this symposium, our current approaches to study the mechanisms how pulmonary LVs are maintained by TGF-β family signals will be discussed.
