Targeting NGF but not VEGF or BDNF signaling reduces endometriosis-associated pain in mice

Tiago H Zaninelli, Victor Fattori, Olivia K Heintz, K. Wright, Philip R. Bennallack, Danielle Sim, Hussain Bukhari, Kathryn L. Terry, Allison F. Vitonis, Stacey A. Missmer, Avacir Casanova Andrello, Raymond M. Anchan, Stephen K. Godin, Dara Bree, Waldiceu A. Verri, Michael S. Rogers
In: bioRxiv · 2023 · doi:10.1101/2023.12.05.570181 · W4389463496
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Abstract

Abstract Introduction Endometriosis is a chronic inflammatory disease that affects ∼10% of women. A significant fraction of patients experience limited or no efficacy with current therapies. Tissue adjacent to endometriosis lesions often exhibits increased neurite and vascular density, suggesting that disease pathology involves neurotrophic activity and angiogenesis. Objectives We aim to evaluate the potential for key tyrosine-kinase-receptor-coupled neurotrophic molecules to contribute to endometriosis-associated pain in mice. Methods The levels of VEGFR1 regulators (VEGFA, VEGFB, PLGF, and sVEGFR1) were quantified by ELISA in peritoneal fluid from endometriosis patients undergoing surgery and used to calculate VEGFR1 occupancy. We used genetic depletion, neutralizing antibody, and pharmacological approaches to specifically block ligand (NGF or BDNF) or neurotrophic receptor (VEGFR1, TRKs) in a murine model of endometriosis-associated pain. Endometriosis-associated pain was determined using the von Frey filaments method, quantification of spontaneous abdominal pain-related behavior, and thermal discomfort. Diseases parameters were evaluated by lesion size and prevalence. Results We found that entrectinib (pan-Trk inhibitor) or anti-NGF treatments reduced evoked pain, spontaneous pain, and thermal discomfort. In contrast, even though receptor occupancy revealing that VEGFR1 agonist levels are sufficient to support pain, blocking VEGFR1 signaling via antibody or tamoxifen-induced knockout did not reduce pain or lesion size in mice. Targeting BDNF-TrkB with an anti-BDNF antibody also proved ineffective. Conclusions This suggests NGF-TrkA signaling, but not BDNF-TrkB or VEGF-VEGFR1, mediates endometriosis-associated pain. Moreover, entrectinib blocks endometriosis-associated pain and reduces lesion sizes. Our results also indicated that entrectinib-like molecules are promising candidates for endometriosis treatment. Credit author statement Conceptualization: T.H. Zaninelli, V. Fattori, and M.S. Rogers; investigation and data curation: T.H. Zaninelli, V. Fattori, O.K. Heintz, K.R. Wright; A.C. Andrello, W.A. Verri Jr, M.S. Rogers; funding acquisition: M.S. Rogers,, S.A. Missmer, R.M. Anchan; methodology: T.H. Zaninelli, V. Fattori, and M.S. Rogers; human sample collection: S.A. Missmer, A.F. Vitonis, K.L. Terry, R.M. Anchan; animal breading and VEGFR1 ablation: D. Sim and H. Bukhari; resources: A.C. Andrello; D. Bree, T. Zheng, J. Wagner, W.A. Verri Jr, and M.S. Rogers; project administration: T.H. Zaninelli; supervision: V. Fattori, W.A. Verri Jr, and M.S. Rogers; visualization: T.H. Zaninelli, V. Fattori, W.A. Verri Jr, and M.S. Rogers; writing–original draft: T.H. Zaninelli; writing – editing and reviewing: all authors. All authors have read and approved the final version of the manuscript.

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endometriosis

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