Sumoylation of Prox1 controls its ability to induce VEGFR3 expression and lymphatic phenotypes in endothelial cells

Pan, Mei-Ren; Chang, Tsung Ming; Chang, Hui; Su, Jen Liang; Wang, Hsei Wei; Hung, Wen Chun

doi:10.1242/jcs.050005

Cited by 54 publications

(55 citation statements)

References 30 publications

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“…By using Alexa-Fluor-564-conjugated siRNA and performing flow cytometry, we determined that the siRNA transfection efficiency was ;85% (data not shown). Quantitative real-time PCR analysis demonstrated that, as expected and in agreement with previous results (Mishima et al 2007;Lee et al 2009;Pan et al 2009), Vegfr3 levels were downregulated when Prox1 is knocked down (Fig. 6A).…”

Section: Vegfr3 Regulates Prox1 Expression In Lec Progenitors and Lecssupporting

confidence: 92%

The Prox1–Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors

et al. 2014

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The mammalian lymphatic vasculature is important for returning fluids from the extracellular tissue milieu back to the blood circulation. We showed previously that Prox1 dosage is important for the development of the mammalian lymphatic vasculature. The lack of Prox1 activity results in the complete absence of lymphatic endothelial cells (LECs). In Prox1 heterozygous embryos, the number of LECs is reduced because of a decrease in the progenitor pool in the cardinal vein. This reduction is caused by some progenitor cells being unable to maintain Prox1 expression. In this study, we identified Vegfr3, the cognate receptor of the lymphangiogenic growth factor Vegfc, as a dosage-dependent, direct in vivo target of Prox1. Using various mouse models, we also determined that Vegfr3 regulates Prox1 by establishing a feedback loop necessary to maintain the identity of LEC progenitors and that Vegfc-mediated activation of Vegfr3 signaling is necessary to maintain Prox1 expression in LEC progenitors. We propose that this feedback loop is the main sensing mechanism controlling the number of LEC progenitors and, as a consequence, the number of budding LECs that will form the embryonic lymphatic vasculature.

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Section: Vegfr3 Regulates Prox1 Expression In Lec Progenitors and Lecssupporting

confidence: 92%

The Prox1–Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors

et al. 2014

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“…A potential mechanism might be that down-regulation of Prox1 that also occurs during acute skin inflammation, at least on the mRNA level (data not shown), directly down-regulates VEGFR-3 expression on the lymphatic endothelium by binding to the VEGFR-3 promoter. [42][43][44][45] Our finding that down-regulation of the lymphaticspecific VEGFR-3 in acute inflammation was comparable in total ear skin (4-fold) and in FACS-isolated lymphatic endothelial cells (5-fold) further confirms its lymphatic-specific expression in the skin. The higher expression of VEGFR-3 in the skin of noninflamed K14-VEGF-C and K14-VEGF-D Tg mice was probably the result of the increased lymphatic vascular network in these mice and not to a specific enhancement of VEGFR-3 expression on lymphatic endothelium.…”

Section: Discussionsupporting

confidence: 66%

An important role of lymphatic vessel activation in limiting acute inflammation

Huggenberger¹,

Siddiqui²,

Brander³

et al. 2011

Blood

218

217

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In contrast to the established role of blood vessel remodeling in inflammation, the biologic function of the lymphatic vasculature in acute inflammation has remained less explored. We studied 2 established models of acute cutaneous inflammation, namely, oxazolone-induced delayed-type hypersensitivity reactions and ultraviolet B irradiation, in keratin 14-vascular endothelial growth factor (VEGF)-C and keratin 14-VEGF-D transgenic mice. These mice have an expanded network of cutaneous lymphatic vessels. Transgenic delivery of the lymphangiogenic factors VEGF-C and the VEGFR-3 specific ligand mouse VEGF-D significantly limited acute skin inflammation in both experimental models, with a strong reduction of dermal edema. Expression of VEGFR-3 by lymphatic endothelium was strongly down-regulated at the mRNA and protein level in acutely inflamed skin, and no VEGFR-3 expression was detectable on inflamed blood vessels and dermal macrophages. There was no major change of the inflammatory cell infiltrate or the composition of the inflammatory cytokine milieu in the inflamed skin of VEGF-C or VEGF-D transgenic mice. However, the increased network of lymphatic vessels in these mice significantly enhanced lymphatic drainage from the ear skin. These results provide evidence that specific lymphatic vessel activation limits acute skin inflammation via promotion of lymph flow from the skin and reduction of edema formation. (Blood. 2011;117(17):4667-4678) IntroductionAcute and chronic inflammatory processes are associated with the growth and/or enlargement of blood and lymphatic vessels. 1 Indeed, vascular remodeling is a hallmark of a plethora of inflammatory diseases, such as chronic airway inflammation, rheumatoid arthritis, inflammatory bowel disease, and the chronic inflammatory skin disease psoriasis. [2][3][4][5] We previously identified an important role of the blood vasculature and in particular of vascular endothelial growth factor (VEGF)-A in the promotion of acute and chronic inflammatory reactions in different experimental skin inflammation models. 6-11 Recently, we found that activation of VEGFR-3 had a potent anti-inflammatory effect in a mouse model of psoriasis. 12 Conversely, inhibition of VEGFR-3 significantly prolonged edema and inflammation during chronic bacterial airway inflammation, in chronic inflammatory arthritis, and in chronic skin inflammation. 3,12,13 However, it has also been reported that the lymphatic vasculature plays an active role in promoting corneal and kidney transplant rejections, in part by facilitating dendritic cell transport to draining lymph nodes. 14,15 Furthermore, the inflamed lymphatic endothelium might actively modulate immune responses. 16,17 Together, these results indicate an important role of blood vessel angiogenesis in sustaining inflammation, whereas the functional role of the lymphatic vasculature in acute inflammation has remained less explored.The cutaneous lymphatic vasculature is involved in the afferent immune response and also maintains tissue fluid homeostasis. [1...

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“…Conversely, overexpression of Prospero causes repression of multiple cell cycle genes and premature termination of cell division (Li and Vaessin 2000). Although Prox1 regulates the expression of CDKN1C/ p57 kip2 , a major cell cycle inhibitor, in LECs as well as other cell types Govindarajan and Overbeek 2001;Petrova et al 2002;Pan et al 2009), there has not been any report detailing cell cycle regulation during Prox1-induced LEC differentiation.…”

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

122

107

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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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Sumoylation of Prox1 controls its ability to induce VEGFR3 expression and lymphatic phenotypes in endothelial cells

Cited by 54 publications

References 30 publications

The Prox1–Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors

The Prox1–Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors

An important role of lymphatic vessel activation in limiting acute inflammation

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

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