Regulation of signaling interactions and receptor endocytosis in growing blood vessels

Pitulescu, Mara E.; Adams, Ralf H.

doi:10.4161/19336918.2014.970010

Cited by 39 publications

(35 citation statements)

References 152 publications

(261 reference statements)

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“…Autophagy may enhance extracellular vesicle/exosome release via the mutivesicular body pathway, especially in serum starved endothelial cells [41, 42]. These pathways may also be relevant for tip/stalk cell specification during sprouting angiogenesis, as tips cells display enhanced VEGFR2 turnover via endocytosis and transfer from early endosomes to multivesicular bodies [42, 43]. Further, Dll4 containing exosomes can be shed from endothelial cells, and Dll4 containing exosomes modulate tip cell phenotype during sprouting angiogenesis [39, 44].…”

Section: Discussionmentioning

confidence: 99%

Release of endothelial cell associated VEGFR2 during TGF-β modulated angiogenesis in vitro

et al. 2017

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BackgroundSprouting angiogenesis requires vascular endothelial proliferation, migration and morphogenesis. The process is regulated by soluble factors, principally vascular endothelial growth factor (VEGF), and via bidirectional signaling through the Jagged/Notch system, leading to assignment of tip cell and stalk cell identity. The cytokine transforming growth factor beta (TGF-β) can either stimulate or inhibit angiogenesis via its differential surface receptor signaling. Here we evaluate changes in expression of angiogenic signaling receptors when bovine aortic endothelial cells were exposed to TGF-β1 under low serum conditions.ResultsTGF-β1 induced a dose dependent inhibition of tip cell assignment and subsequent angiogenesis on Matrigel, maximal at 5.0 ng/ml. This occurred via ALK5-dependent pathways and was accompanied by significant upregulation of the TGF-β co-receptor endoglin, and SMAD2 phosphorylation, but no alteration in Smad1/5 activation. TGF-β1 also induced ALK5-dependent downregulation of Notch1 but not of its ligand delta-like ligand 4. Cell associated VEGFR2 (but not VEGFR1) was significantly downregulated and accompanied by reciprocal upregulation of VEGFR2 in conditioned medium. Quantitative polymerase chain reaction analysis revealed that this soluble VEGFR2 was not generated by a selective shift in mRNA isoform transcription. This VEGFR2 in conditioned medium was full-length protein and was associated with increased soluble HSP-90, consistent with a possible shedding of microvesicles/exosomes.ConclusionsTaken together, our results suggest that endothelial cells exposed to TGF-β1 lose both tip and stalk cell identity, possibly mediated by loss of VEGFR2 signaling. The role of these events in physiological and pathological angiogenesis requires further investigation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12860-017-0127-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Release of endothelial cell associated VEGFR2 during TGF-β modulated angiogenesis in vitro

et al. 2017

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“…The VEGF-induced internalization of VEGFR2 is dependent on clathrin-mediated receptor endocytosis (35)(36)(37). Accordingly, clathrin knockdown has been shown to reduce VEGFR2 autophosphorylation (35).…”

Section: R-ras Inhibits Phosphorylation Of Vegfr2 At All Major Tyrosimentioning

confidence: 99%

“…R-Ras Inhibits VEGF-dependent VEGFR2 Internalization-VEGF ligand binding induces the clathrin-dependent internalization of VEGFR2, and this internalization is required for the full activation of VEGFR2 (35)(36)(37). Because all major tyrosine autophosphorylation sites are down-regulated simultaneously by R-Ras, we investigated the effect of R-Ras on VEGFR2 internalization upon VEGF stimulation of ECs.…”

Section: R-ras Inhibits Phosphorylation Of Vegfr2 At All Major Tyrosimentioning

confidence: 99%

R-Ras Protein Inhibits Autophosphorylation of Vascular Endothelial Growth Factor Receptor 2 in Endothelial Cells and Suppresses Receptor Activation in Tumor Vasculature

Sawada

Komatsu

2015

Journal of Biological Chemistry

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“…VEGF expression is considered to be an important indicator of the development of new microvessels which can also promote angiogenesis in wound healing (11)(12)(13). In order to test the effects of the various vein treatments on the flow-through skin flap grafts, western blot analysis was performed to determine the expression levels of VEGF on day 5 (Figs.…”

Section: Resultsmentioning

confidence: 99%

Effects of preserving different veins on flow-through flap survival: An experimental study

Song

2015

Experimental and Therapeutic Medicine

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Abstract. Flow-through skin flap grafting is becoming widely used for the reconstruction of skin and soft tissue defects, particularly for patients with poor blood supply around the defect. However, the treatment of the veins remains controversial. In the present study, 5x2-cm skin flaps were created on the left inner thighs of rabbits in order to investigate the effects of various treatments of the veins on the survival of a flow-through skin flap. A femoral artery perforator running through the flap was preserved. Five groups were established in which no veins, one superficial vein (SV), one accompanying vein (AV), one SV plus one AV, or all trunk veins (control) were retained. The percentage of flap area survival was determined on day 10. On days 3, 5, 7 and 9, tissues were harvested from the skin flaps and immunohistochemical analysis was performed in order to count the number of microvessels. Western blot analysis was subsequently completed in order to determine the expression levels of vascular endothelial growth factor (VEGF). The flap areas in which no veins were retained demonstrated significantly reduced survival rates on day 10, as compared with those in the other four groups (P<0.01). Furthermore, flaps with the retention of a SV also demonstrated reduced survival rates, as compared with the AV, AV plus SV and all veins groups (P<0.01); however, there no significant differences were detected between the latter three groups (P>0.05). Immunohistochemical analysis on day 3 detected a greater number of microvessels in the flaps of the control group, as compared with the flaps of the other groups. Furthermore, the AV and AV plus SV groups demonstrated a greater number of microvessels, as compared with the SV and no vein groups, and he no vein group demonstrated the fewest microvessels. No significant differences were found between the AV, AV plus SV and control groups on day 5, 7 and 9. Western blot analysis on day 5 demonstrated that the expression levles of VEGF were significantly increased in the flaps of the AV, AV plus SV and control groups, as compared with those in the SV and no vein groups. No significant differences were detected between the former three groups, and increased VEGF expression levels were detected in the flaps of the SV group, as compared with the no vein group. The flow-through flap grafts with no retained veins barely survived. Anastomosing one AV was adequate for flap survival; however, further studies are required in order to investigate the survival of flow-through flaps in more detail.

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Regulation of signaling interactions and receptor endocytosis in growing blood vessels

Cited by 39 publications

References 152 publications

Release of endothelial cell associated VEGFR2 during TGF-β modulated angiogenesis in vitro

Release of endothelial cell associated VEGFR2 during TGF-β modulated angiogenesis in vitro

R-Ras Protein Inhibits Autophosphorylation of Vascular Endothelial Growth Factor Receptor 2 in Endothelial Cells and Suppresses Receptor Activation in Tumor Vasculature

Effects of preserving different veins on flow-through flap survival: An experimental study

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