Postnatal Deletion of Podoplanin in Lymphatic Endothelium Results in Blood Filling of the Lymphatic System and Impairs Dendritic Cell Migration to Lymph Nodes

Bianchi, Roberta; Russo, Erica; Bachmann, Stephan; Proulx, Steven T.; Sesartić, Marko; Smaadahl, Nora; Watson, Steve P.; Buckley, Christopher D.; Halin, Cornelia; Detmar, Michael

doi:10.1161/atvbaha.116.308020

Cited by 43 publications

(37 citation statements)

References 47 publications

(71 reference statements)

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“…Podoplanin deficiency impairs cardiac development [59], while continuous expression of podoplanin into adulthood is required to maintain functional lymphatic vasculature [57, 62, 63]. Accordingly, we detected the presence of canonical lymphendothelial markers Prox-1 and VEGFR-3 within the cohort of podoplanin-positive LYVE-1-negative cells (Table 1), which might be indicative of their differentiation into lymphatic endothelial cells of CLVs.…”

Section: Discussionmentioning

confidence: 81%

Phenotypically heterogeneous podoplanin-expressing cell populations are associated with the lymphatic vessel growth and fibrogenic responses in the acutely and chronically infarcted myocardium

et al. 2017

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Cardiac lymphatic vasculature undergoes substantial expansion in response to myocardial infarction (MI). However, there is limited information on the cellular mechanisms mediating post-MI lymphangiogenesis and accompanying fibrosis in the infarcted adult heart. Using a mouse model of permanent coronary artery ligation, we examined spatiotemporal changes in the expression of lymphendothelial and mesenchymal markers in the acutely and chronically infarcted myocardium. We found that at the time of wound granulation, a three-fold increase in the frequency of podoplanin-labeled cells occurred in the infarcted hearts compared to non-operated and sham-operated counterparts. Podoplanin immunoreactivity detected LYVE-1-positive lymphatic vessels, as well as masses of LYVE-1-negative cells dispersed between myocytes, predominantly in the vicinity of the infarcted region. Podoplanin-carrying populations displayed a mesenchymal progenitor marker PDGFRα, and intermittently expressed Prox-1, a master regulator of the lymphatic endothelial fate. At the stages of scar formation and maturation, concomitantly with the enlargement of lymphatic network in the injured myocardium, the podoplanin-rich LYVE-1-negative multicellular assemblies were apparent in the fibrotic area, aligned with extracellular matrix deposits, or located in immediate proximity to activated blood vessels with high VEGFR-2 content. Of note, these podoplanin-containing cells acquired the expression of PDGFRβ or a hematoendothelial epitope CD34. Although Prox-1 labeling was abundant in the area affected by MI, the podoplanin-presenting cells were not consistently Prox-1-positive. The concordance of podoplanin with VEGFR-3 similarly varied. Thus, our data reveal previously unknown phenotypic and structural heterogeneity within the podoplanin-positive cell compartment in the infarcted heart, and suggest an alternate ability of podoplanin-presenting cardiac cells to generate lymphatic endothelium and pro-fibrotic cells, contributing to scar development.

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Section: Discussionmentioning

confidence: 81%

Phenotypically heterogeneous podoplanin-expressing cell populations are associated with the lymphatic vessel growth and fibrogenic responses in the acutely and chronically infarcted myocardium

et al. 2017

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“…The bioactivity of VEGF-C and VEGF-D is can be inhibited by soluble VEGFR2 (sVEGFR2) and sVEGFR3 that modulate extracellular growth factor gradients. Other LEC markers include Podoplanin, which binds platelet-derived CLEC-2 138 , and LYmphatic VEssel hyaluronan receptor (LYVE-1), which binds hyaluronan. LECs also express many other common transmembrane growth factor receptors including fibroblast growth factor receptor (FGFR1), angiopoietin receptors Tie1/Tie2, and transforming growth factor β receptor (TGFβR).…”

Section: Box 1 Molecular Regulation Of Lymphangiogenesismentioning

confidence: 99%

Cardiac lymphatics in health and disease

2018

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The lymphatic vasculature, which accompanies the blood vasculature in most organs, is indispensable in for maintenance of tissue fluid homeostasis, immune cell trafficking and nutritional lipid uptake and transport, as well as reverse cholesterol transport. In this review, we discuss the physiological role of lymphatics in the heart, in maintenance of cardiac health, and describe alterations of lymphatic structure and function that occur in cardiovascular pathology, including atherosclerosis and myocardial infarction. We further discuss briefly the role that immune cells may play in the regulation of lymphatic growth (lymphangiogenesis) and function. Finally, we provide recent examples of how the cardiac lymphatics may be targeted therapeutically to restore lymphatic drainage in the heart in order to limit myocardial edema and chronic inflammation. Key points  Cardiac lymphatics display a dynamic range of fluid uptake and transport, linked to cardiac contractility and heart rate  Cardiac lymphatics undergo significant remodeling in several cardiovascular diseases, which can alter the lymphatic drainage capacity in the heart  Insufficient lymphangiogenesis may contribute to the buildup of atherosclerotic lesions in large arteries due to accumulation of both lipids and activated immune cells  Immune cells contribute to the process of lymphatic remodeling by stimulating or inhibiting lymphangiogenesis  Therapeutic stimulation of cardiac lymphangiogenesis after myocardial infarction leads to accelerated resolution of myocardial edema and inflammation, promoting cardiac recovery

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“…The interaction of podoplanin and platelet CLEC-2 has been proposed to prevent retrograde flow of blood from the venous system by supporting activation of platelets on the lymphatic valves (80,81). This would suggest that the lymphatic valves on their own are unable to form a sufficiently tight seal to counteract the higher pressure in the venous system.…”

mentioning

confidence: 99%