VEGFR3 Modulates Vascular Permeability by Controlling VEGF/VEGFR2 Signaling

Heinolainen, Krista; Karaman, Sinem; D’Amico, Gabriela; Tammela, Tuomas; Sormunen, Raija; Eklund, Lauri; Alitalo, Kari; Zarkada, Georgia

doi:10.1161/circresaha.116.310477

Cited by 131 publications

(108 citation statements)

References 49 publications

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“…As binding of VEGF‐C to VEGFR‐3 has been reported to alter the intrinsic and phasic pumping of collecting lymphatics in rat mesentery,76 our results reveal that apoA‐I could promote lymphatic integrity through the upregulation of VEGFR‐3 activity. Of interest, a recent article reported that VEGFR‐3 prevented excessive vascular permeability by limiting VEGFR‐2 expression and VEGF/VEGFR‐2 pathway activity in quiescent and angiogenic blood vascular endothelial cells 77. Whether and how VEGFR‐3 could modulate its own expression to subsequently regulate lymphatic contraction capacity remains to be tested.…”

Section: Discussionmentioning

confidence: 99%

“…Of interest, a recent article reported that VEGFR-3 prevented excessive vascular permeability by limiting VEGFR-2 expression and VEGF/VEGFR-2 pathway activity in quiescent and angiogenic blood vascular endothelial cells. 77 Whether and how VEGFR-3 could modulate its own expression to subsequently regulate lymphatic contraction capacity remains to be tested.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Milasan

Jean

Dallaire

et al. 2017

JAHA

View full text Add to dashboard Cite

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“…Astrocytes have been identified as modulators of the BBB permeability, for instance through the release of VEGF-A in response to neuroinflammation 27 . Activation of the vascular endothelial growth factor receptors (VEGFRs) is a key regulator of the endothelial/vascular permeability both in vitro 28 and in vivo 29 . Therefore, VEGF-A supplements in the medium activate the VEGFR2 on the endothelial cells, which induces the phosphorylation of adherens junction proteins such as VE-cadherin 30 .…”

Section: Discussionmentioning

confidence: 99%

Predicting In Vivo Payloads Delivery using a Blood-brain Tumor-barrier in a Dish

Joncour

Karaman

Laakkonen

2019

JoVE

Self Cite

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Highly selective by nature, the blood-brain barrier (BBB) is essential for the brain homeostasis in physiological conditions. However, in the context of brain tumors, the molecular selectivity of BBB also shields the neoplastic cells by blocking the delivery of peripherally administered chemotherapies. The development of novel drugs (including nanoparticles) targeting malignant brain tumors ideally requires the use of preclinical animal models to study the drug's transcytosis and antitumor efficacy. In order to comply with the 3R principle (refine, reduce, and replace) to reduce the number of laboratory animals in experimental setup and perform the high-throughput screening of a large library of antitumor agents, we developed a reproducible in vitro human and murine mimic of the blood-brain tumor-barrier (BBTB) using three-layered cultures of endothelial cells, astrocytes, and patient-derived glioblastoma spheres. For higher scalability and reproducibility, commercial cell lines or immortalized cells have been used in tailored conditions to allow the formation of a barrier resembling the actual BBB. Here we describe a protocol to obtain a BBTB mimic by culturing endothelial cells in contact with astrocytes at specific cell densities on inserts. This BBTB mimic can be used, for instance, for the quantification and confocal imaging of the nanoparticle passage through the endothelial and astrocytic barriers, in addition to the evaluation of the tumor cell targeting within the same assay. Moreover, we show that the obtained data can be used to predict the behavior of nanoparticles in preclinical animal models. In a broader perspective, this in vitro model could be adapted to other neurodegenerative diseases for the determination of the passage of new therapeutic molecules through the BBB and/or be supplemented with brain organoids to directly evaluate the efficacy of drugs.

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“…These hemizygote Myr-Venus embryos were used for histological analysis of hyaluronan metabolism. ICR males and females (8)(9)(10)(11)(12) week old;…”

Section: Methodsmentioning

confidence: 99%

“…The decidual mesometrial pole, on the other hand, is characterized by the development of vascular sinuous folds (VSFs), which are arterio-venous vascular shunts, markedly enlarged and elongated prior to placentation 8 . Another receptor for VEGF signaling, VEGFR-3, participates in this orchestrated series of events as an attenuator of vascular permeability by inhibiting VEGFR-2 expression, consequently blocking VEGF-VEGFR-2 induced permeability 12,13 . Perturbation of vascular remodeling during early pregnancy is associated with pathologies, often detected at later stages of gestation, including firsttrimester miscarriages, preeclampsia, placental failure and intrauterine growth restriction 8 .…”

Section: Introductionmentioning

confidence: 99%

Hyaluronan-NK cell Interaction Controls the Primary Vascular Barrier during Early Pregnancy

Hadas

Gershon

Cohen

et al. 2020

Preprint

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Successful implantation is associated with a unique spatial pattern of vascular remodeling, characterized by profound peripheral neo-vascularization surrounding a periembryo avascular niche. We hypothesized that hyaluronan controls the formation of the unique vascular pattern encompassing the embryo. This hypothesis was evaluated by genetic modification of hyaluronan metabolism specifically targeted to embryonic trophoblast cells. The outcome of altered hyaluronan deposition on uterine vascular remodeling and post-implantation development were analyzed by MRI, detailed histological examinations, and RNA-sequencing of uterine NK cells. Our experiments revealed that eliminating the anti-angiogenic hyaluronan, led to elevated expression of MMP-9, VEGF-A and its receptor VEGFR-2, accompanied by reduced recruitment of uterine NK cells. Further local decrease in VEGFR-3 resulted in impaired formation of vascular sinuous folds, ectopic angiogenesis and dysfunctional uterine NK cells.Conversely, enhanced deposition of hyaluronan caused the expansion of the maternalembryo barrier, leading to an increased diffusion distance and aborted implantation.These results demonstrate a pivotal role for hyaluronan in successful pregnancy by finetuning the peri-embryo avascular niche and maternal vascular morphogenesis.

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VEGFR3 Modulates Vascular Permeability by Controlling VEGF/VEGFR2 Signaling

Abstract: VEGFR3 limits VEGFR2 expression and VEGF/VEGFR2 pathway activity in quiescent and angiogenic blood vascular endothelial cells, thereby preventing excessive vascular permeability.

Cited by 131 publications

References 49 publications

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

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

Predicting In Vivo Payloads Delivery using a Blood-brain Tumor-barrier in a Dish

Hyaluronan-NK cell Interaction Controls the Primary Vascular Barrier during Early Pregnancy

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