RESUMO
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)-ß/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.
Assuntos
Receptores de Activinas Tipo II/metabolismo , Fator 2 de Diferenciação de Crescimento/metabolismo , Vasos Linfáticos/fisiologia , Neovascularização Patológica/fisiopatologia , Neovascularização Fisiológica/fisiologia , Peritonite/fisiopatologia , Transdução de Sinais/fisiologia , Análise de Variância , Animais , Primers do DNA/genética , Diafragma/patologia , Perfilação da Expressão Gênica , Células HEK293 , Técnicas Histológicas , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
In addition to fluid and lipid absorption, immune cell trafficking has now become recognized as one of the major functions of the lymphatic system. Recently, several critical roles of the lymphatic vessels (LVs) in modulating immune reactions during both physiological and pathological conditions have been emerging. As LVs serve as conduits for immune cells, they come to closely interact with macrophages/monocytes, dendritic cells, and T and B lymphocytes. Accumulating evidences indicate that reciprocal interactions between the LVs and immune cells exist which cause considerable influence over the process of immune cell migration, LV growth, and ultimately certain immune reactions. This chapter discusses on the interactions of macrophages/monocytes and dendritic cells with peripheral LVs and on those of sinusoidal macrophages and T and B lymphocytes with lymph node LVs.