Dataset Information

Platelet-mediated angiogenesis is independent of VEGF and fully inhibited by aspirin.

ABSTRACT:

Background and purpose

Platelets are major players in every step of vessel development through the local delivery of angiogenesis-modulating factors, including the pro-angiogenic protein VEGF and the anti-angiogenic endostatin. Although thrombin is a potent agonist and is highly elevated in angiogenesis-related diseases, studies regarding its action on the release of platelet angiogenic factors are scarce and controversial. Herein, we have investigated the role of thrombin not only in VEGF and endostatin release but also in net platelet angiogenic activity.

Experimental approach

Human platelets were stimulated with thrombin in the presence of the various inhibitors of the signalling pathways involved in platelet activation. Supernatants/releasates were used to determine the levels of angiogenic molecules and to induce angiogenic responses.

Key results

We found that thrombin induced the secretion of both VEGF and endostatin; however, the overall effect of the releasates was pro-angiogenic as they promoted tubule-like formation and increased the proliferation of endothelial cells. Both responses were only slightly suppressed in the presence of a VEGF receptor-neutralizing antibody. Pharmacological studies revealed that while inhibitors of PKC, p38, ERK1/2, Src kinases or PI3K/Akt exerted only partial inhibitory effects, aspirin fully blocked the pro-angiogenic activity of the releasate.

Conclusions and implications

In contrast to current belief, platelet pro-angiogenic responses are independent of VEGF and appear to be the result of the combined action of several molecules. Moreover, our data reinforce the notion that aspirin is a good candidate for a therapeutic agent to treat angiogenesis-related diseases.

SUBMITTER: Etulain J

PROVIDER: S-EPMC3834751 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Publications

Platelet-mediated angiogenesis is independent of VEGF and fully inhibited by aspirin.

Etulain J J Fondevila C C Negrotto S S Schattner M M

British journal of pharmacology 20130901 2

<h4>Background and purpose</h4>Platelets are major players in every step of vessel development through the local delivery of angiogenesis-modulating factors, including the pro-angiogenic protein VEGF and the anti-angiogenic endostatin. Although thrombin is a potent agonist and is highly elevated in angiogenesis-related diseases, studies regarding its action on the release of platelet angiogenic factors are scarce and controversial. Herein, we have investigated the role of thrombin not only in VE ...[more]

PMID: 23713888

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Project description:Non?small cell lung cancer (NSCLC) accounts for over 80% of all diagnosed lung cancer cases. Lung cancer is the leading cause of cancer?related deaths worldwide. Most NSCLC cells overexpress vascular endothelial growth factor?A (VEGF?A) which plays a pivotal role in tumour angiogenesis. Anti?angiogenic therapies including VEGF?A neutralisation have significantly improved the response rates, progression?free survival and overall survival of patients with NSCLC. However, the median survival of these patients is shorter than 18 months, suggesting that NSCLC cells secrete VEGF?independent angiogenic factors, which remain unknown. We aimed to explore these factors in human NSCLC cell lines, A549, Lu99 and EBC?1 using serum?free culture, to which only EBC?1 cells could adapt. By mass spectrometry, we identified 1,007 proteins in the culture supernatant derived from EBC?1 cells. Among the identified proteins, interleukin?8 (IL?8), macrophage migration inhibitory factor (MIF), galectin?1, midkine (MK), IL?18, galectin?3, VEGF?A, hepatoma?derived growth factor (HDGF), osteopontin (OPN), connective tissue growth factor (CTGF) and granulin (GRN) are known to be involved in angiogenesis. Tube formation, neutralisation and RNA interference assays revealed that VEGF?A and HDGF function as angiogenic factors in EBC?1 cells. To confirm whether VEGF?A and HDGF also regulate angiogenesis in the other NSCLC cell lines, we established a novel culture method. NSCLC cells were embedded in collagen gel and cultured three?dimensionally. Tube formation, neutralisation and RNA interference assays using the three?dimensional (3D) culture supernatant showed that VEGF?A and HDGF were not angiogenic factors in Lu99 cells. By gene microarray in EBC?1 and Lu99 cells, we identified 61 mRNAs expressed only in Lu99 cells. Among these mRNAs, brain?derived neurotrophic factor (BDNF), fibroblast growth factor?2 (FGF?2) and FGF?5 are known to be involved in angiogenesis. Tube formation and neutralisation assays clarified that FGF?2 functions as an angiogenic factor in Lu99 cells. These results indicate that HDGF enhances VEGF?dependent angiogenesis and that FGF?2 is a VEGF?independent angiogenic factor in human NSCLC cells.

Dataset Information

Platelet-mediated angiogenesis is independent of VEGF and fully inhibited by aspirin.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Platelet-mediated angiogenesis is independent of VEGF and fully inhibited by aspirin.

Similar Datasets

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