Platelet Activation Receptor CLEC-2 Regulates Blood/Lymphatic Vessel Separation by Inhibiting Proliferation, Migration, and Tube Formation of Lymphatic Endothelial Cells

Osada, Makoto; Ito, Osamu; Ding, Guohua; Shirai, Toshiaki; Ichise, Hirotake; Hirayama, Kazuyoshi; Takano, Katsuhiro; Yatomi, Yutaka; Hirashima, Masanori; Fujii, Hideki; Suzuki‐Inoue, Katsue; Ozaki, Yukio

doi:10.1074/jbc.m111.329987

Cited by 143 publications

(166 citation statements)

References 51 publications

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“…Some groups have reported that platelet activation by CLEC2 signaling may regulate LEC growth in vitro through secretion of platelet granule contents (6,10). However, we have not observed such effects on LEC growth in vitro or detected major defects in the pattern or rate of lymphatic vascular development in vivo (8,11), and how such an angiogenic mechanism would explain an ongoing requirement in mature, presumably nonangiogenic, animals is not clear.…”

Section: Introductioncontrasting

confidence: 64%

Platelets mediate lymphovenous hemostasis to maintain blood-lymphatic separation throughout life

Hess¹,

Rawnsley²,

Jakus³

et al. 2013

J. Clin. Invest.

185

217

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Mammals transport blood through a high-pressure, closed vascular network and lymph through a lowpressure, open vascular network. These vascular networks connect at the lymphovenous (LV) junction, where lymph drains into blood and an LV valve (LVV) prevents backflow of blood into lymphatic vessels. Here we describe an essential role for platelets in preventing blood from entering the lymphatic system at the LV junction. Loss of CLEC2, a receptor that activates platelets in response to lymphatic endothelial cells, resulted in backfilling of the lymphatic network with blood from the thoracic duct (TD) in both neonatal and mature mice. Fibrin-containing platelet thrombi were observed at the LVV and in the terminal TD in wild-type mice, but not Clec2-deficient mice. Analysis of mice lacking LVVs or lymphatic valves revealed that platelet-mediated thrombus formation limits LV backflow under conditions of impaired valve function. Examination of mice lacking integrin-mediated platelet aggregation indicated that platelet aggregation stabilizes thrombi that form in the lymphatic vascular environment to prevent retrograde blood flow. Collectively, these studies unveil a newly recognized form of hemostasis that functions with the LVV to safeguard the lymphatic vascular network throughout life.

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Section: Introductioncontrasting

confidence: 64%

Platelets mediate lymphovenous hemostasis to maintain blood-lymphatic separation throughout life

Hess¹,

Rawnsley²,

Jakus³

et al. 2013

J. Clin. Invest.

185

217

View full text Add to dashboard Cite

show abstract

“…Interestingly, it has been shown that during embryogenesis, lymphatic system separation from blood vessels requires platelet activity 7. Indeed, platelets regulate the blood/lymphatic vessel separation by inhibiting the proliferation, migration, and tube formation of LECs, upon the interaction of C‐type lectin‐like receptor 2 (CLEC‐2) with podoplanin 8. Platelet activity has also been shown to be required throughout life in order to maintain the lymphovenous junction integrity 5.…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein A‐I Modulates Atherosclerosis Through Lymphatic Vessel‐Dependent Mechanisms in Mice

Milasan

Jean

Dallaire

et al. 2017

JAHA

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BackgroundSubcutaneously injected lipid‐free apoA‐I (apolipoprotein A‐I) reduces accumulation of lipid and immune cells within the aortic root of hypercholesterolemic mice without increasing high‐density lipoprotein–cholesterol concentrations. Lymphatic vessels are now recognized as prerequisite players in the modulation of cholesterol removal from the artery wall in experimental conditions of plaque regression, and particular attention has been brought to the role of the collecting lymphatic vessels in early atherosclerosis‐related lymphatic dysfunction. In the present study, we address whether and how preservation of collecting lymphatic function contributes to the protective effect of apoA‐I.Methods and ResultsAtherosclerotic Ldlr −/− mice treated with low‐dose lipid‐free apoA‐I showed enhanced lymphatic transport and abrogated collecting lymphatic vessel permeability in atherosclerotic Ldlr −/− mice when compared with albumin‐control mice. Treatment of human lymphatic endothelial cells with apoA‐I increased the adhesion of human platelets on lymphatic endothelial cells, in a bridge‐like manner, a mechanism that could strengthen endothelial cell–cell junctions and limit atherosclerosis‐associated collecting lymphatic vessel dysfunction. Experiments performed with blood platelets isolated from apoA‐I‐treated Ldlr −/− mice revealed that apoA‐I decreased ex vivo platelet aggregation. This suggests that in vivo apoA‐I treatment limits platelet thrombotic potential in blood while maintaining the platelet activity needed to sustain adequate lymphatic function.ConclusionsAltogether, we bring forward a new pleiotropic role for apoA‐I in lymphatic function and unveil new potential therapeutic targets for the prevention and treatment of atherosclerosis.

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“…26 More recently, Osada et al proposed that during embryonic development, podoplanin in LECs activates platelets by binding to CLEC-2 in the connection between lymph sacs and CV and that inhibits migration, proliferation, and tube formation, which facilitates blood/lymphatic vessel separation. 27 In any case, our description that podoplanin expression only starts after LECs leave the CV is probably an indication of the LEC maturation process. Our findings emphasize the idea that the process of LEC differentiation is a stepwise process that starts in the veins but continues after the LEC progenitors leave the CV.…”

Section: Discussionmentioning

confidence: 77%

Lymphatic endothelial progenitors bud from the cardinal vein and intersomitic vessels in mammalian embryos

Yang

García‐Verdugo

Soriano-Navarro

et al. 2012

Blood

198

196

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The lymphatic vasculature preserves tissue fluid balance by absorbing fluid and macromolecules and transporting them to the blood vessels for circulation. The stepwise process leading to the formation of the mammalian lymphatic vasculature starts by the expression of the gene Prox1 in a subpopulation of blood endothelial cells (BECs) on the cardinal vein (CV) at approximately E9.5. These Prox1-expressing lymphatic endothelial cells (LECs) will exit the CV to form lymph sacs, primitive structures from which the entire lymphatic network is derived. Until now, no conclusive information was available regarding the cellular processes by which these LEC progenitors exit the CV without compromising the vein's integrity. We determined that LECs leave the CV by an active budding mechanism. During this process, LEC progenitors are interconnected by VE-cadherin-expressing junctions. Surprisingly, we also found that Prox1-expressing LEC progenitors were present not only in the CV but also in the intersomitic vessels (ISVs). Furthermore, as LEC progenitors bud from the CV and ISVs into the surrounding mesenchyme, they begin expressing the lymphatic marker podoplanin, migrate away from the CV, and form the lymph sacs. Analyzing this process in Prox1-null embryos revealed that Prox1 activity is necessary for LEC progenitors to exit the CV. (Blood. 2012;120(11):2340-2348) IntroductionOur understanding of the genes and mechanisms controlling the development of the mammalian lymphatic vasculature has greatly advanced in the last decade. The results of targeted inactivation experiments in mice have identified 3 transcription factors (Prox1, Sox18, and COUP-TFII) as crucial regulators of early lymphatic endothelial cell (LEC) differentiation in mammals; their functional inactivation results in a complete lack of LECs and, therefore, of the entire lymphatic vasculature. [1][2][3][4] It is generally accepted that the initiation of Prox1 expression in a subpopulation of venous endothelial cells (VECs) in the wall of the mouse cardinal vein (CV) at around E9.5 is one of the earliest steps during mammalian lymphatic vasculature formation. We have previously shown that the embryonic veins are the unique source of the entire mammalian lymphatic vasculature by showing that Prox1-expressing LECs that exit the CV form the embryonic lymph sacs from which the entire lymphatic vasculature is eventually derived. 2,5 Although it is known that in mammals Vegfc signaling is required for LECs to exit the CV, 6 until now no conclusive data were available regarding the cellular mechanisms involved in this critical process. For instance, how do these endothelial cells (ECs) exit the CV? How is it that LECs leave the CV without disrupting the endothelial barrier? To address some of these important questions, we performed electron microscopy (EM) to visualize Prox1-expressing LEC progenitors leaving the CV. Results from these analyses determined that Prox1-expressing LEC progenitors leave the CV by budding and that the integrity of the CV is not compromi...

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Platelet Activation Receptor CLEC-2 Regulates Blood/Lymphatic Vessel Separation by Inhibiting Proliferation, Migration, and Tube Formation of Lymphatic Endothelial Cells

Cited by 143 publications

References 51 publications

Platelets mediate lymphovenous hemostasis to maintain blood-lymphatic separation throughout life

Platelets mediate lymphovenous hemostasis to maintain blood-lymphatic separation throughout life

Apolipoprotein A‐I Modulates Atherosclerosis Through Lymphatic Vessel‐Dependent Mechanisms in Mice

Lymphatic endothelial progenitors bud from the cardinal vein and intersomitic vessels in mammalian embryos

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