Targeting VEGFR1 on endothelial progenitors modulates their differentiation potential

d’Audigier, Clément; Gautier, Benoît; Yon, Alexis; Alili, Jean-Meidi; Guérin, Coralie L.; Evrard, Solène; Godiér, Anne; Haviari, Skerdi; Marie, Reille-Serroussi,; Huguenot, Florent; Dizier, Blandine; Inguimbert, Nicolas; Borgel, Delphine; Bièche, Ivan; Boisson-Vidal, Catherine; Roncal, Carmen; Carmeliet, Peter; Vidal, Michel; Gaussem, Pascale; Smadja, David M.

doi:10.1007/s10456-013-9413-2

Cited by 14 publications

(8 citation statements)

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“…Several of the VEGFR1 functions that have been identified are in non-ECs (33,34,35,36,37,38) , and endothelial specific VEGFR1 functions remain uncertain. Our experimental data showed that VEGF 165 b-inhibition induces VEGFR1-activation not VEGFR2 or its downstream signaling in Balb/c ischemic muscle.…”

Section: Discussionmentioning

confidence: 99%

VEGF ₁₆₅ b Modulates Endothelial VEGFR1–STAT3 Signaling Pathway and Angiogenesis in Human and Experimental Peripheral Arterial Disease

Ganta

Choi

Kutateladze

et al. 2017

Circulation Research

118

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Rationale Atherosclerotic-arterial occlusions decrease tissue perfusion causing ischemia to lower limbs in patients with peripheral arterial disease (PAD). Ischemia in muscle induces an angiogenic response but the magnitude of this response is frequently inadequate to meet tissue perfusion requirements. Alternate splicing in the exon-8 of vascular endothelial growth factor (VEGF)-A results in production of pro-angiogenic VEGFxxxa isoforms (VEGF165a, 165 for the 165 amino acid product) and anti-angiogenic VEGFxxxb (VEGF165b) isoforms. Objective The anti-angiogenic VEGFxxxb isoforms are thought to antagonize VEGFxxxa isoforms and decrease activation of VEGF-Receptor-2 (VEGFR2), hereunto considered the dominant receptor in post-natal angiogenesis in PAD. Our data will show that VEGF165b inhibits VEGFR1-Signal Transducer and Activator of Transcription (STAT)-3 signaling to decrease angiogenesis in human and experimental PAD. Methods and Results In human PAD vs. control muscle-biopsies, VEGF165b: a) is elevated, b) is bound higher (vs. VEGF165a) to VEGFR1 not VEGFR2, and c) levels correlated with decreased VEGFR1, not VEGFR2, activation. In experimental PAD, delivery of an isoform specific monoclonal antibody (Ab) to VEGF165b vs. control-Ab enhanced perfusion in animal model of severe PAD (Balb/c strain) without activating VEGFR2-signaling but with increased VEGFR1-activation. Receptor pull-down experiments demonstrate that VEGF165b-inhibition vs. control increased VEGFR1-STAT3 binding and STAT3-activation, independent of janus activated kinase (Jak1)/Jak2. Using VEGFR1+/− mice that could not increase VEGFR1 after ischemia, we confirm that VEGF165b decreases VEGFR1-STAT3 signaling to decrease perfusion. Conclusions Our results indicate that VEGF165b prevents activation of VEGFR1-STAT3 signaling by VEGF165a and hence inhibits angiogenesis and perfusion recovery in PAD muscle.

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Section: Discussionmentioning

confidence: 99%

VEGF ₁₆₅ b Modulates Endothelial VEGFR1–STAT3 Signaling Pathway and Angiogenesis in Human and Experimental Peripheral Arterial Disease

Ganta

Choi

Kutateladze

et al. 2017

Circulation Research

118

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“…PlGF also binds to the neuropilin-1/VEGF165 receptor and stimulates angiogenesis [14]. Since its discovery in 1991 [15], PlGF has been associated with a number of disease states [16] including ischaemia [17], cardiovascular disease [18], cancer [19], arthritis [20] and preeclampsia [21]. Recent reports have revealed that there is increased secretion of PlGF from ECFCs isolated from end-stage renal failure patients [22] while in-vitro exposure to PlGF can enhance tubulogenic function in ECFCs [18].…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-induced responses by endothelial colony-forming cells are modulated by placental growth factor

et al. 2016

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BackgroundEndothelial colony-forming cells (ECFCs), also termed late outgrowth endothelial cells, are a well-defined circulating endothelial progenitor cell type with an established role in vascular repair. ECFCs have clear potential for cell therapy to treat ischaemic disease, although the precise mechanism(s) underlying their response to hypoxia remains ill-defined.MethodsIn this study, we isolated ECFCs from umbilical cord blood and cultured them on collagen. We defined the response of ECFCs to 1% O2 exposure at acute and chronic time points.ResultsIn response to low oxygen, changes in ECFC cell shape, proliferation, size and cytoskeleton phenotype were detected. An increase in the number of senescent ECFCs also occurred as a result of long-term culture in 1% O2. Low oxygen exposure altered ECFC migration and tube formation in Matrigel®. Increases in angiogenic factors secreted from ECFCs exposed to hypoxia were also detected, in particular, after treatment with placental growth factor (PlGF). Exposure of cells to agents that stabilise hypoxia-inducible factors such as dimethyloxalylglycine (DMOG) also increased PlGF levels. Conditioned medium from both hypoxia-treated and DMOG-treated cells inhibited ECFC tube formation. This effect was reversed by the addition of PlGF neutralising antibody to the conditioned medium, confirming the direct role of PlGF in this effect.ConclusionsThis study deepens our understanding of the response of ECFCs to hypoxia and also identifies a novel and important role for PlGF in regulating the vasculogenic potential of ECFCs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0430-0) contains supplementary material, which is available to authorized users.

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“…The medium from Cell Applications is a defined medium containing a combination of EGF, FGF2 and VEGF. Specifically, VEGF promotes outgrowth of endothelial cell colonies from circulating endothelial progenitor cells (d’Audigier et al 2014) and thus, may be important for the attachment of single cells and the initiation of proliferation.…”

Section: Discussionmentioning

confidence: 99%

Outgrowth, proliferation, viability, angiogenesis and phenotype of primary human endothelial cells in different purchasable endothelial culture media: feed wisely

Leopold

Strutz

Weiss

et al. 2019

Histochem Cell Biol

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Function and dysfunction of endothelial cells are regulated by a multitude of factors. Endothelial cell research often requires in vitro cell culture experiments. Hence, various culture media specifically designed to promote endothelial cell growth are available. These strikingly differ in their composition: complex media contain endothelial cell growth supplement (ECGS), an extract produced of bovine brain with undefined amounts of biologically active compounds, whilst defined media contain selected growth factors in defined concentrations. We here compared the effect of seven purchasable endothelial cell culture media on colony outgrowth, proliferation, viability, in vitro angiogenesis and phenotype of mature primary human endothelial cells using feto-placental endothelial cells isolated from chorionic arteries (fpEC). The effect of media on colony outgrowth was additionally tested on umbilical cord blood-derived endothelial progenitor cells (ECFCs). Outgrowth, purity, proliferation and viability differed between media. Outgrowth of fpEC and ECFCs was best in a defined medium containing EGF, FGF2 and VEGF. By contrast, established fpEC isolations proliferated best in complex media containing ECGS, heparin and ascorbic acid. Also viability of cells was higher in complex media. In vitro angiogenesis was most intense in a defined medium containing the highest number of individual growth factors. FACS analysis of surface markers for endothelial cell subtypes revealed that endothelial phenotype of fpEC was unaffected by media composition. Our data demonstrate the fundamental effect of endothelial cell culture media on primary cell isolation success and behaviour. Whether the composition of supplements is suitable also for individual experiments needs to be tested specifically.Electronic supplementary materialThe online version of this article (10.1007/s00418-019-01815-2) contains supplementary material, which is available to authorized users.

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Targeting VEGFR1 on endothelial progenitors modulates their differentiation potential

Abstract: PlGF plasma levels were found increased in cardiovascular patients. Disrupting PlGF/VEGFR1 pathway could modulate ECFC-induced tubulogenesis, the cell type responsible for newly formed vessels in vivo.

Cited by 14 publications

References 57 publications

VEGF ₁₆₅ b Modulates Endothelial VEGFR1–STAT3 Signaling Pathway and Angiogenesis in Human and Experimental Peripheral Arterial Disease

VEGF ₁₆₅ b Modulates Endothelial VEGFR1–STAT3 Signaling Pathway and Angiogenesis in Human and Experimental Peripheral Arterial Disease

Hypoxia-induced responses by endothelial colony-forming cells are modulated by placental growth factor

Outgrowth, proliferation, viability, angiogenesis and phenotype of primary human endothelial cells in different purchasable endothelial culture media: feed wisely

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Targeting VEGFR1 on endothelial progenitors modulates their differentiation potential

Abstract: PlGF plasma levels were found increased in cardiovascular patients. Disrupting PlGF/VEGFR1 pathway could modulate ECFC-induced tubulogenesis, the cell type responsible for newly formed vessels in vivo.

Cited by 14 publications

References 57 publications

VEGF 165 b Modulates Endothelial VEGFR1–STAT3 Signaling Pathway and Angiogenesis in Human and Experimental Peripheral Arterial Disease

VEGF 165 b Modulates Endothelial VEGFR1–STAT3 Signaling Pathway and Angiogenesis in Human and Experimental Peripheral Arterial Disease

Hypoxia-induced responses by endothelial colony-forming cells are modulated by placental growth factor

Outgrowth, proliferation, viability, angiogenesis and phenotype of primary human endothelial cells in different purchasable endothelial culture media: feed wisely

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VEGF ₁₆₅ b Modulates Endothelial VEGFR1–STAT3 Signaling Pathway and Angiogenesis in Human and Experimental Peripheral Arterial Disease

VEGF ₁₆₅ b Modulates Endothelial VEGFR1–STAT3 Signaling Pathway and Angiogenesis in Human and Experimental Peripheral Arterial Disease