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Inhibition of VEGF receptors induces pituitary apoplexy: An experimental study in mice

Anti-vascular endothelial growth factor (VEGF) therapy has been developed for the treatment of a variety of cancers. Although this therapy may be a promising alternative treatment for refractory pituitary adenomas and pituitary carcinomas, the effects of anti-VEGF agents on the pituitary gland are n...

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Autores principales: Sugita, Yoshito, Takada, Shigeki, Tanigaki, Kenji, Muraki, Kazue, Uemura, Munehiro, Hojo, Masato, Miyamoto, Susumu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10019612/
https://www.ncbi.nlm.nih.gov/pubmed/36928058
http://dx.doi.org/10.1371/journal.pone.0279634
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author Sugita, Yoshito
Takada, Shigeki
Tanigaki, Kenji
Muraki, Kazue
Uemura, Munehiro
Hojo, Masato
Miyamoto, Susumu
author_facet Sugita, Yoshito
Takada, Shigeki
Tanigaki, Kenji
Muraki, Kazue
Uemura, Munehiro
Hojo, Masato
Miyamoto, Susumu
author_sort Sugita, Yoshito
collection PubMed
description Anti-vascular endothelial growth factor (VEGF) therapy has been developed for the treatment of a variety of cancers. Although this therapy may be a promising alternative treatment for refractory pituitary adenomas and pituitary carcinomas, the effects of anti-VEGF agents on the pituitary gland are not yet well understood. Here, we found that mice administered with OSI-930, an inhibitor of receptor tyrosine kinases including VEGF receptor 1 and 2, frequently exhibited hemorrhage in the pituitary gland. This is the first report that anti-VEGF therapy can cause pituitary apoplexy. C57BL/6 mice were daily injected intraperitoneally with 100 mg/kg body weight of OSI-930 for one to six days. Pituitary glands were immunohistochemically examined. Four of six mice treated for three days and all of five mice treated for six days exhibited hemorrhage in the pituitary gland. In all cases, the hemorrhage occurred just around Rathke’s cleft. In OSI-930-administered mice, the vascular coverage and branching were reduced in the anterior lobe, and capillary networks were also decreased in the intermediate lobe in a treatment-day dependent manner. Few blood vessels around Rathke’s cleft of the intermediate lobe express VE-cadherin and are covered with platelet-derived growth factor receptor-β (PDGFR-β)-positive cells, which suggests that capillaries around Rathke’s cleft of the intermediate lobe were VE-cadherin-negative and not covered with pericytes. The reduction of capillary plexus around Rathke’s cleft was observed at the site where hemorrhage occurred, suggesting a causal relationship with the pathogenesis of pituitary hemorrhage. Our study demonstrates that anti-VEGF agents have a risk of pituitary apoplexy. Pituitary apoplexy should be kept in mind as an adverse effect of anti-VEGF therapy.
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spelling pubmed-100196122023-03-17 Inhibition of VEGF receptors induces pituitary apoplexy: An experimental study in mice Sugita, Yoshito Takada, Shigeki Tanigaki, Kenji Muraki, Kazue Uemura, Munehiro Hojo, Masato Miyamoto, Susumu PLoS One Research Article Anti-vascular endothelial growth factor (VEGF) therapy has been developed for the treatment of a variety of cancers. Although this therapy may be a promising alternative treatment for refractory pituitary adenomas and pituitary carcinomas, the effects of anti-VEGF agents on the pituitary gland are not yet well understood. Here, we found that mice administered with OSI-930, an inhibitor of receptor tyrosine kinases including VEGF receptor 1 and 2, frequently exhibited hemorrhage in the pituitary gland. This is the first report that anti-VEGF therapy can cause pituitary apoplexy. C57BL/6 mice were daily injected intraperitoneally with 100 mg/kg body weight of OSI-930 for one to six days. Pituitary glands were immunohistochemically examined. Four of six mice treated for three days and all of five mice treated for six days exhibited hemorrhage in the pituitary gland. In all cases, the hemorrhage occurred just around Rathke’s cleft. In OSI-930-administered mice, the vascular coverage and branching were reduced in the anterior lobe, and capillary networks were also decreased in the intermediate lobe in a treatment-day dependent manner. Few blood vessels around Rathke’s cleft of the intermediate lobe express VE-cadherin and are covered with platelet-derived growth factor receptor-β (PDGFR-β)-positive cells, which suggests that capillaries around Rathke’s cleft of the intermediate lobe were VE-cadherin-negative and not covered with pericytes. The reduction of capillary plexus around Rathke’s cleft was observed at the site where hemorrhage occurred, suggesting a causal relationship with the pathogenesis of pituitary hemorrhage. Our study demonstrates that anti-VEGF agents have a risk of pituitary apoplexy. Pituitary apoplexy should be kept in mind as an adverse effect of anti-VEGF therapy. Public Library of Science 2023-03-16 /pmc/articles/PMC10019612/ /pubmed/36928058 http://dx.doi.org/10.1371/journal.pone.0279634 Text en © 2023 Sugita et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Sugita, Yoshito
Takada, Shigeki
Tanigaki, Kenji
Muraki, Kazue
Uemura, Munehiro
Hojo, Masato
Miyamoto, Susumu
Inhibition of VEGF receptors induces pituitary apoplexy: An experimental study in mice
title Inhibition of VEGF receptors induces pituitary apoplexy: An experimental study in mice
title_full Inhibition of VEGF receptors induces pituitary apoplexy: An experimental study in mice
title_fullStr Inhibition of VEGF receptors induces pituitary apoplexy: An experimental study in mice
title_full_unstemmed Inhibition of VEGF receptors induces pituitary apoplexy: An experimental study in mice
title_short Inhibition of VEGF receptors induces pituitary apoplexy: An experimental study in mice
title_sort inhibition of vegf receptors induces pituitary apoplexy: an experimental study in mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10019612/
https://www.ncbi.nlm.nih.gov/pubmed/36928058
http://dx.doi.org/10.1371/journal.pone.0279634
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