Rapamycin reversal of VEGF-C–driven lymphatic anomalies in the respiratory tract

Bałuk, Peter; Yao, Li‐Chin; Flores, Julio C.; Choi, Dongwon; Hong, Young‐Kwon; McDonald, Donald M.

doi:10.1172/jci.insight.90103

Cited by 44 publications

(52 citation statements)

References 84 publications

(152 reference statements)

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“…In the present study, either complete inactivation of VEGFR3 in VEGFR3 iΔLEC mice or < 50% reduction of VEGF‐C in ABX‐treated mice was sufficient to reduce lacteal length to the same extent. While VEGF‐C retains its dose‐dependent effect on the lymphangiogenesis after birth , haploinsufficiency of VEGFR3 did not show distinct phenotypes, compared to the WT mice . Therefore, 50% reduction of VEGF‐C mRNA level should not be equal to 50% reduction of VEGFR3 mRNA level.…”

Section: Discussionmentioning

confidence: 89%

Gut microbiota regulates lacteal integrity by inducing VEGF‐C in intestinal villus macrophages

et al. 2019

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A lacteal is a blunt‐ended, long, tube‐like lymphatic vessel located in the center of each intestinal villus that provides a unique route for drainage of absorbed lipids from the small intestine. However, key regulators for maintaining lacteal integrity are poorly understood. Here, we explore whether and how the gut microbiota regulates lacteal integrity. Germ depletion by antibiotic treatment triggers lacteal regression during adulthood and delays lacteal maturation during the postnatal period. In accordance with compromised lipid absorption, the button‐like junction between lymphatic endothelial cells, which is ultrastructurally open to permit free entry of dietary lipids into lacteals, is significantly reduced in lacteals of germ‐depleted mice. Lacteal defects are also found in germ‐free mice, but conventionalization of germ‐free mice leads to normalization of lacteals. Mechanistically, VEGF‐C secreted from villus macrophages upon MyD88‐dependent recognition of microbes and their products is a main factor in lacteal integrity. Collectively, we conclude that the gut microbiota is a crucial regulator for lacteal integrity by endowing its unique microenvironment and regulating villus macrophages in small intestine.

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Section: Discussionmentioning

confidence: 89%

Gut microbiota regulates lacteal integrity by inducing VEGF‐C in intestinal villus macrophages

et al. 2019

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“…3). This might be explainable by the report that dual inhibition of mTOR and vascular endothelial growth factor (VEGF) pathway by sirolimus in lymphatic anomalies 27 . Both pathways played a vital role in lymphangiogenesis 27,28 .…”

Section: Discussionmentioning

confidence: 99%

“…This might be explainable by the report that dual inhibition of mTOR and vascular endothelial growth factor (VEGF) pathway by sirolimus in lymphatic anomalies 27 . Both pathways played a vital role in lymphangiogenesis 27,28 . Sirolimus treatment also inhibited the expression of VEGFR‐3 and VEGF‐C, the potent growth factors for lymphatic endothelial cells 17,29,30 .…”

Section: Discussionmentioning

confidence: 99%

Analysis of mTOR pathway expression in lymphatic malformation and related diseases

Hori

Ozeki

Hirose

et al. 2020

Pathology International

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The mammalian target of rapamycin (mTOR) inhibitor sirolimus is an effective treatment for difficult‐to‐treat lymphatic anomalies. However, little is known about the expression of mTOR pathway components in lymphatic anomalies. Here we investigated the expression pattern of mTOR pathway components and their phosphorylated forms (mTOR, p‐mTOR, 4EBP1, p‐4EBP1, S6K1 and p‐S6K1) in normal lymphatic vessels and lymphatic anomalies using immunohistochemistry. We studied 18 patients of lymphatic anomalies, including lymphatic malformation (LM, n = 14), Kaposiform lymphangiomatosis (KLA, n = 2) and Kaposiform hemangioendothelioma (KHE, n = 2). Normal lymphatic vessels expressed 4EBP1, S6K1 and p‐S6K1, but not p‐4EBP1, mTOR or p‐mTOR. The mTOR was detected in all lymphatic anomalies, whereas its activation form p‐mTOR was detected in half cases of KLA and KHE but not in LM. All lymphatic anomalies expressed S6K1 and its activated form p‐S6K1. The expression of 4EBP1 was also found in all lymphatic anomalies, but its activation was detected in approximately half of them. The activation of mTOR was seen in tumor (KLA and KHE) but not in malformation (LM), whereas the activation of S6K1 and 4EBP1 was seen in all and half of lymphatic anomalies, respectively.

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“…Nonetheless, many genetic, pharmacologic, and other powerful experimental tools underscore the value of studies of lymphatics in mice. Although the understanding of lymphatics in mouse lungs is still at an early stage [1], reports have described the distribution of lymphatics under normal conditions and changes in lymphatics of mouse airways or lungs after administration of noxious substances [2–4] or infectious organisms [5–11], transgenic overexpression of VEGF-C or interleukin-1beta [12–14], effects of rapamycin [13], and lung transplantation [15]. Here, we describe materials and methods that have been found to be useful for visualizing by fluorescence and confocal microscopy the lymphatics in mouse lungs under normal conditions and in models of disease.…”

Section: Introductionmentioning

confidence: 99%

Imaging Lymphatics in Mouse Lungs

Bałuk

McDonald

2018

Methods in Molecular Biology

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Lymphatic malformations and other conditions where lymphatic function is disturbed in the respiratory tract present diagnostic and therapeutic challenges. Advances in lymphatic development, growth regulation, function, and imaging have increased the understanding of lymphatics, but the airways and lungs have not received as much attentions as many other organs. The lung presents challenges for studies of lymphatics because of the complex, densely packed three-dimensional architecture of the airways and vasculature, and because it cannot readily be examined in its entirety. To address this problem, we developed methods for immunohistochemical examination of the lymphatics in mouse lungs, based on approaches we devised for lymphatic vessels and blood vessels in whole mounts of the mouse trachea. This report provides a practical guide for visualizing by fluorescence and confocal microscopy the lymphatics in mouse airways and lungs under normal conditions and in models of disease. Materials and methods are described for immunohistochemical staining of lymphatics in whole mounts of the mouse trachea and 200-μm sections of mouse lung. Also described are mouse models in which lymphatics proliferate in the lung, blocking antibodies for preventing lymphatic growth, methods for fixing mouse lungs by vascular perfusion, and techniques for staining, visualizing, and analyzing lymphatic endothelial cells and other cells in the lung. These methods provide the opportunity to learn as much about lymphatics in the lung as in other organs.

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Rapamycin reversal of VEGF-C–driven lymphatic anomalies in the respiratory tract

Cited by 44 publications

References 84 publications

Gut microbiota regulates lacteal integrity by inducing VEGF‐C in intestinal villus macrophages

Gut microbiota regulates lacteal integrity by inducing VEGF‐C in intestinal villus macrophages

Analysis of mTOR pathway expression in lymphatic malformation and related diseases

Imaging Lymphatics in Mouse Lungs

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