Inhibition of endogenous TGF-β signaling enhances lymphangiogenesis

Oka, Masako; Iwata, Caname; Suzuki, Hiroshi; Kiyono, Kunihiko; Morishita, Yasuyuki; Watabe, Tetsuro; Komuro, Akiyoshi; Kano, Mitsunobu R.; Miyazono, Kohei

doi:10.1182/blood-2007-10-120337

Cited by 202 publications

(201 citation statements)

References 50 publications

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“…In lens epithelium, nuclear accumulation of Smad4 has been implicated in the regulation of Prox1 expression (31). In addition, we previously reported that TGF-β also inhibited the proliferation of HDLECs in vitro and lymphangiogenesis in vivo (12). Notably, TGF-β also downregulates PROX1 expression in HDLECs.…”

Section: Discussionmentioning

confidence: 94%

“…Although many factors have been identified as prolymphangiogenic factors, there have been few reports on endogenous antilymphangiogenic factors. In addition to interferon-γ (11), we previously reported that TGF-β is a negative regulator of lymphangiogenesis (12). Although both these inhibitors decrease Prox1 expression, the molecular mechanisms and physiological relevance of their actions remain to be understood.…”

Section: Significancementioning

confidence: 99%

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

Yoshimatsu

Lee

Akatsu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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107

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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

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Section: Discussionmentioning

confidence: 94%

Section: Significancementioning

confidence: 99%

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

Yoshimatsu

Lee

Akatsu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

107

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“…In addition to Sox18, NF-kb (Flister et al 2010(Flister et al , 2011, TGF-b (Oka et al 2008), interleukin-3 (Groger et al 2004), and VEGF-C (Sivakumar et al 2008) have been shown to regulate Prox1 in endothelial cells, but their roles in lymphatic development need to be established. Moreover, regulators of Prox1 have been reported in other types of cells.…”

Section: Prox1: the Master Regulator For Lymphatic Developmentmentioning

confidence: 99%

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

Choi

Lee²,

Hong

2012

Cold Spring Harbor Perspectives in Medicine

117

106

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The blood and lymphatic systems are the two major circulatory systems in our body. Although the blood system has been studied extensively, the lymphatic system has received much less scientific and medical attention because of its elusive morphology and mysterious pathophysiology. However, a series of landmark discoveries made in the past decade has begun to change the previous misconception of the lymphatic system to be secondary to the more essential blood vascular system. In this article, we review the current understanding of the development and pathology of the lymphatic system. We hope to convince readers that the lymphatic system is no less essential than the blood circulatory system for human health and well-being.

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“…In addition to inhibiting the proliferation and migration of human dermal lymphatic microvascular endothelial cells, TGF-decreases the expression of LECrelated genes, including Prox1 and Lyve1, in these cells. Moreover, TGF R-I inhibitor potentiates lymphangiogenesis in the presence of VEGF-C in vivo (Oka et al 2008). …”

Section: Other Regulators Of Lymphatic Vascular Developmentmentioning

confidence: 99%

Developmental and pathological lymphangiogenesis: from models to human disease

Hajjami

Petrova

2008

Histochem Cell Biol

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The lymphatic vascular system, the body's second vascular system present in vertebrates, has emerged in recent years as a crucial player in normal and pathological processes. It participates in the maintenance of normal tissue Xuid balance, the immune functions of cellular and antigen traYcking and absorption of fatty acids and lipidsoluble vitamins in the gut. Recent scientiWc discoveries have highlighted the role of lymphatic system in a number of pathologic conditions, including lymphedema, inXammatory diseases, and tumor metastasis. Development of genetically modiWed animal models, identiWcation of lymphatic endothelial speciWc markers and regulators coupled with technological advances such as high-resolution imaging and genome-wide approaches have been instrumental in understanding the major steps controling growth and remodeling of lymphatic vessels. This review highlights the recent insights and developments in the Weld of lymphatic vascular biology.

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Inhibition of endogenous TGF-β signaling enhances lymphangiogenesis

Cited by 202 publications

References 50 publications

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

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

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

Developmental and pathological lymphangiogenesis: from models to human disease

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