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VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms

Background: Chronic inflammation has been recognized in neoplastic disorders, including myeloproliferative neoplasm (MPN), as an important regulator of angiogenesis. Aims: We investigated the influence of vascular endothelial growth factor (VEGF) and pro-inflammatory interleukin-6 (IL-6) on the expr...

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Autores principales: Subotički, Tijana, Mitrović Ajtić, Olivera, Živković, Emilija, Diklić, Miloš, Đikić, Dragoslava, Tošić, Milica, Beleslin-Čokić, Bojana, Dragojević, Teodora, Gotić, Mirjana, Santibanez, Juan F., Čokić, Vladan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268588/
https://www.ncbi.nlm.nih.gov/pubmed/34206393
http://dx.doi.org/10.3390/ijms22136671
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author Subotički, Tijana
Mitrović Ajtić, Olivera
Živković, Emilija
Diklić, Miloš
Đikić, Dragoslava
Tošić, Milica
Beleslin-Čokić, Bojana
Dragojević, Teodora
Gotić, Mirjana
Santibanez, Juan F.
Čokić, Vladan
author_facet Subotički, Tijana
Mitrović Ajtić, Olivera
Živković, Emilija
Diklić, Miloš
Đikić, Dragoslava
Tošić, Milica
Beleslin-Čokić, Bojana
Dragojević, Teodora
Gotić, Mirjana
Santibanez, Juan F.
Čokić, Vladan
author_sort Subotički, Tijana
collection PubMed
description Background: Chronic inflammation has been recognized in neoplastic disorders, including myeloproliferative neoplasm (MPN), as an important regulator of angiogenesis. Aims: We investigated the influence of vascular endothelial growth factor (VEGF) and pro-inflammatory interleukin-6 (IL-6) on the expression of angiogenic factors, as well as inflammation-related signaling in mononuclear cells (MNC) of patients with MPN and JAK2V617F positive human erythroleukemic (HEL) cells. Results: We found that IL-6 did not change the expression of angiogenic factors in the MNC of patients with MPN and HEL cells. However, IL-6 and the JAK1/2 inhibitor Ruxolitinib significantly increased angiogenic factors—endothelial nitric oxide synthase (eNOS), VEGF, and hypoxia-inducible factor-1 alpha (HIF-1α)—in patients with polycythemia vera (PV). Furthermore, VEGF significantly increased the expression of HIF-1α and eNOS genes, the latter inversely regulated by PI3K and mTOR signaling in the MNC of primary myelofibrosis (PMF). VEGF and inhibitors of inflammatory JAK1/2, PI3K, and mTOR signaling reduced the eNOS protein expression in HEL cells. VEGF also decreased the expression of eNOS and HIF-1α proteins in the MNC of PMF. In contrast, VEGF increased eNOS and HIF-1α protein expression in the MNC of patients with PV, which was mediated by the inflammatory signaling. VEGF increased the level of IL-6 immunopositive MNC of MPN. In summary, VEGF conversely regulated gene and protein expression of angiogenic factors in the MNC of PMF, while VEGF increased angiogenic factor expression in PV mediated by the inflammation-related signaling. Conclusion: The angiogenic VEGF induction of IL-6 supports chronic inflammation that, through positive feedback, further promotes angiogenesis with concomitant JAK1/2 inhibition.
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spelling pubmed-82685882021-07-10 VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms Subotički, Tijana Mitrović Ajtić, Olivera Živković, Emilija Diklić, Miloš Đikić, Dragoslava Tošić, Milica Beleslin-Čokić, Bojana Dragojević, Teodora Gotić, Mirjana Santibanez, Juan F. Čokić, Vladan Int J Mol Sci Article Background: Chronic inflammation has been recognized in neoplastic disorders, including myeloproliferative neoplasm (MPN), as an important regulator of angiogenesis. Aims: We investigated the influence of vascular endothelial growth factor (VEGF) and pro-inflammatory interleukin-6 (IL-6) on the expression of angiogenic factors, as well as inflammation-related signaling in mononuclear cells (MNC) of patients with MPN and JAK2V617F positive human erythroleukemic (HEL) cells. Results: We found that IL-6 did not change the expression of angiogenic factors in the MNC of patients with MPN and HEL cells. However, IL-6 and the JAK1/2 inhibitor Ruxolitinib significantly increased angiogenic factors—endothelial nitric oxide synthase (eNOS), VEGF, and hypoxia-inducible factor-1 alpha (HIF-1α)—in patients with polycythemia vera (PV). Furthermore, VEGF significantly increased the expression of HIF-1α and eNOS genes, the latter inversely regulated by PI3K and mTOR signaling in the MNC of primary myelofibrosis (PMF). VEGF and inhibitors of inflammatory JAK1/2, PI3K, and mTOR signaling reduced the eNOS protein expression in HEL cells. VEGF also decreased the expression of eNOS and HIF-1α proteins in the MNC of PMF. In contrast, VEGF increased eNOS and HIF-1α protein expression in the MNC of patients with PV, which was mediated by the inflammatory signaling. VEGF increased the level of IL-6 immunopositive MNC of MPN. In summary, VEGF conversely regulated gene and protein expression of angiogenic factors in the MNC of PMF, while VEGF increased angiogenic factor expression in PV mediated by the inflammation-related signaling. Conclusion: The angiogenic VEGF induction of IL-6 supports chronic inflammation that, through positive feedback, further promotes angiogenesis with concomitant JAK1/2 inhibition. MDPI 2021-06-22 /pmc/articles/PMC8268588/ /pubmed/34206393 http://dx.doi.org/10.3390/ijms22136671 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Subotički, Tijana
Mitrović Ajtić, Olivera
Živković, Emilija
Diklić, Miloš
Đikić, Dragoslava
Tošić, Milica
Beleslin-Čokić, Bojana
Dragojević, Teodora
Gotić, Mirjana
Santibanez, Juan F.
Čokić, Vladan
VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms
title VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms
title_full VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms
title_fullStr VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms
title_full_unstemmed VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms
title_short VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms
title_sort vegf regulation of angiogenic factors via inflammatory signaling in myeloproliferative neoplasms
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268588/
https://www.ncbi.nlm.nih.gov/pubmed/34206393
http://dx.doi.org/10.3390/ijms22136671
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