Inhibition of TP signaling promotes endometriosis growth and neovascularization

Akiko Furue, Kyoko Hattori, Kanako Hosono, Mina Tanabe, Erina Sato, Masako Honda, Kazuki Sekiguchi, Yoshiya Ito, Masataka Majima, Shuh Narumiya, Kazuyoshi Kato, Hideki Amano
Molecular medicine reports · 2023 · vol. 28(4) · doi:10.3892/mmr.2023.13079 · PMID:37654213 · W4386293791
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⚙ AI-generated summary by claude@2026-06, 2026-06-09 ⓘ

Inhibition of thromboxane prostanoid receptor signaling in a mouse model promotes endometriosis implant growth, angiogenesis, and lymphangiogenesis, partly by altering macrophage polarization.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-09 ⓘ

The paper examined whether inhibiting thromboxane (TX) synthase/TP (thromboxane prostanoid) receptor signaling affects endometriosis development and the formation of new blood and lymphatic vessels using a mouse endometrial transplantation model with ovariectomized recipients. Female TP-deficient mice and pharmacological TXS inhibition (ozagrel) were used, and implant size at day 14 together with vascular markers (CD31/VEGFR2 and LYVE-1) plus VEGF-A, VEGF-C, VEGF-D, COX-2–related prostanoid context, and inflammatory macrophage (F4/80) signaling were assessed by histology/immunostaining, quantitative PCR, and macrophage cell culture with U46619 and lipopolysaccharide. Inhibition of TP signaling reduced implant growth and decreased angiogenesis and lymphangiogenesis-associated readouts in the endometrial implants. A key caveat stated implicitly by the design is that effects were evaluated at a single post-implant time point (day 14) in an ectopic transplantation model, rather than longitudinal progression, which may limit interpretation of dynamics. This paper is centrally about endometriosis — it tests how TP signaling and its inhibition regulate endometriosis growth and neovascularization/lymphangiogenesis in mouse lesions.

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Abstract

Endometriosis is highly dependent on angiogenesis and lymphangiogenesis. Prostaglandin E2, an arachidonic acid metabolite, has been shown to promote the formation of new blood and lymphatic vessels. However, the role of another arachidonic acid metabolite, thromboxane A2 (TXA2) in angiogenesis and lymphangiogenesis during endometriosis remains largely unexplored. Using a murine model of ectopic endometrial transplantation, fragments from the endometrium of WT donor mice were transplanted into the peritoneal walls of recipient WT mice (WT→WT), resulting in an increase in both the area and density of blood and lymphatic vessels. Upon transplantation of endometrial tissue from thromboxane prostanoid (TP) receptor (TXA2 receptor)‑deficient (TP‑/‑) mice into TP‑/‑ mice (TP‑/‑→TP‑/‑), an increase in implant growth, angiogenesis, and lymphangiogenesis were observed along with upregulation of pro‑angiogenic and lymphangiogenic factors, including vascular endothelial growth factors (VEGFs). Similar results were obtained using a thromboxane synthase (TXS) inhibitor in WT→WT mice. Furthermore, TP‑/‑→TP‑/‑ mice had a higher number of F4/80+ cells than that of WT→WT mice, with increased expression of genes related to the anti‑inflammatory macrophage phenotype in endometrial lesions. In cultured bone marrow (BM)‑derived macrophages, the levels of VEGF‑A, VEGF‑C, and VEGF‑D decreased in a TP‑dependent manner. Furthermore, TP signaling affected the polarization of cultured BM‑derived macrophages to the anti‑inflammatory phenotype. These findings imply that inhibition of TP signaling promotes endometrial implant growth and neovascularization.

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Condition tags

mesh:D004715endometriosis

MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Prostaglandins Prostaglandins Prostaglandins Prostaglandins Prostaglandins Prostaglandins Prostaglandins Prostaglandins Receptors, Thromboxane A2, Prostaglandin H2 Receptors, Thromboxane A2, Prostaglandin H2 Receptors, Thromboxane A2, Prostaglandin H2 Receptors, Thromboxane A2, Prostaglandin H2

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