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Review
. 2024 Mar;29(3):43.
doi: 10.3892/mmr.2024.13167. Epub 2024 Jan 19.

Angiogenesis signaling in endometriosis: Molecules, diagnosis and treatment (Review)

Caixia Bo  1 , Yunfei Wang  2
Affiliations
Review

Angiogenesis signaling in endometriosis: Molecules, diagnosis and treatment (Review)

Caixia Bo et al. Mol Med Rep. 2024 Mar.

Abstract

Endometriosis (EM) is one of the most common diseases among women of reproductive age. The etiology and pathogenesis of EM remain unclear and therefore there is a lack of effective treatment measures, which affects physical and mental health, as well as the quality of life of patients with EM. Angiogenesis has become a hotspot for research on the pathogenesis of EM; the role of angiogenesis‑related serological markers and anti‑angiogenic therapy in the diagnosis and treatment of EM is promising for early diagnosis and treatment of EM. Angiogenesis in EM is subject to complex regulation by hormones, immunity and associated cytokines. Therefore, novel targets for angiogenesis therapy are also being discovered and developed. The present review summarized the pathological mechanisms of angiogenesis and the value of relevant markers in pathogenesis and diagnosis of EM, along with the status of research on anti‑angiogenic drugs in the treatment of EM. The role of angiogenesis in EM provides an important reference for treatment and diagnosis, but there is no uniform non‑invasive diagnostic marker and proven strategy for anti‑angiogenesis.

Keywords: angiogenesis; anti‑angiogenic; biomarkers; diagnosis; endometriosis.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1.
Figure 1.
Angiogenic microenvironment of EM based on Sampson's retrograde menstruation theory, in which viable endothelial cells reflux into the peritoneal cavity. Under peritoneal hypoxia and altered immuno-inflammatory microenvironment, defective immune surveillance occurs, leading to imbalance of immune cells and secretion of relevant cytokines, which promotes ectopic endothelial colonization, adhesion and neovascularization. Ang, angiopoietin; IL, interleukin; FGF, fibroblast growth factor; MMIF, macrophage migration inhibitory factor; VEGF, vascular endothelial growth factor; COX-2, cyclooxygenase 2; TNF-α, tumor necrosis factor-α.
Figure 2.
Figure 2.
Molecular pathways of angiogenic signaling in EM. Angiogenesis is associated with a variety of factors, including abdominal microenvironment and immunomodulatory imbalance. In hypoxic conditions, ROS release and VEGF expression are enhanced. ROS can induce oxidative stress, which drives the activation of genes downstream of NF-κB signaling, induces inflammatory responses and regulates the expression of cytokines such as IL-8 and COX-2, which regulates angiogenesis. In addition, there is a positive feedback mechanism between ROS and VEGF, which contributes to angiogenesis. The interaction of the inflammatory response with cytokines can mediate differentiation of immune cells, which in turn exacerbates imbalance of the abdominal microenvironment and angiogenesis of the ectopic endothelium. EM, endometriosis; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor; NF-κB, nuclear factor-κB; IL, interleukin; COX-2, cyclooxygenase 2; COUP-TFII, COUP transcription factor 2; Ang, angiopoietin; HIF-1α, hypoxia-inducible factor-1α; PGE2, prostaglandin E2; NOS, nitric oxide synthase; MMP, matrix metalloproteinase; CCL-2, C-C motif chemokine ligand 2; TNF-α, tumor necrosis factor-α; LPS, lipopolysaccharide.
Figure 3.
Figure 3.
Basis of action of anti-angiogenic drugs in EM. (1) Anti-VEGF drugs such as bevacizumab and sorafenib. (2) COX-2 inhibitors such as celecoxib and parecoxib. (3) Angiotensin II receptor blockers such as telmisartan. (4) Immunomodulators such as etanercept and rapamycin. (5) Antioxidants such as melatonin and resveratrol. (6) NF-κB inhibitors such as BAY11-7085 and pyrrolidine dithiocarbamate. (7) Other drugs such as cabergoline and quinagolide. EM, endometriosis; VEGF, vascular endothelial growth factor; COX-2, cyclooxygenase 2; NF-κB, nuclear factor-κB; IL, interleukin; ANG, angiotensin; TNF-α, tumor necrosis factor-α; MMIF, macrophage migration inhibitory factor; Ang, angiopoietin; FGF, fibroblast growth factor; HIF-1α, hypoxia-inducible factor-1α.
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References

    1. Smolarz B, Szyłło K, Romanowicz H. Endometriosis: Epidemiology, classification, pathogenesis, treatment and genetics (Review of Literature) Int J Mol Sci. 2021;22:10554. doi: 10.3390/ijms221910554. - DOI - PMC - PubMed
    1. Samimi M, Pourhanifeh MH, Mehdizadehkashi A, Eftekhar T, Asemi Z. The role of inflammation, oxidative stress, angiogenesis, and apoptosis in the pathophysiology of endometriosis: Basic science and new insights based on gene expression. J Cell Physiol. 2019;234:19384–19392. doi: 10.1002/jcp.28666. - DOI - PubMed
    1. Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med. 2020;382:1244–1256. doi: 10.1056/NEJMra1810764. - DOI - PubMed
    1. Brasil DL, Montagna E, Trevisan CM, La Rosa VL, Laganà AS, Barbosa CP, Bianco B, Zaia V. Psychological stress levels in women with endometriosis: Systematic review and meta-analysis of observational studies. Minerva Med. 2020;111:90–102. doi: 10.23736/S0026-4806.19.06350-X. - DOI - PubMed
    1. Sullivan-Myers C, Sherman KA, Beath AP, Duckworth TJ, Cooper MJW. Delineating sociodemographic, medical and quality of life factors associated with psychological distress in individuals with endometriosis. Hum Reprod. 2021;36:2170–2180. doi: 10.1093/humrep/deab138. - DOI - PubMed

Grants and funding

The present study was supported by The National Natural Science Foundation of China (grant no. 81502255), Shandong Provincial Traditional Chinese Medicine Science and Technology Development Project (grant no. M-2022242) and the Key R&D Program of Jining (grant nos. 2020YXNS026 and 2022YXNS007).