# Oxidative Stress Mediated by Macrophages Promotes Angiogenesis and Early Development of Endometriosis

## TL;DR

Macrophage-driven oxidative stress promotes early endometriosis development through increased angiogenesis, suggesting anti-inflammatory and antioxidant therapies may be effective.

## Contribution

This study identifies the Alox15 pathway and HIF-1α signaling as key in macrophage-mediated oxidative stress and neovascularization in early endometriosis.

## Key findings

- Macrophage depletion reduces oxidative stress, lesion size, and neovascularization in endometriosis.
- Inactivation of Alox15 similarly reduces oxidative stress and lesion growth.
- HIF-1α inhibition confirms its role in neovascularization and lesion progression.

## Abstract

Endometriosis is a hormone-dependent gynecological disease manifested by cyclic pelvic pain and female infertility. Although many studies have shown that neoangiogenesis plays an essential role in the development of early endometriosis, the underlying pathophysiological mechanisms remain unclear. Recent evidence suggests that macrophages play an important role in the pathogenesis of endometriosis and that the hypoxia-inducible factor-1alpha (HIF-1α) may be involved, but when and how are largely unknown. Herein, we explore the role of macrophages in the early development of endometriosis using an in vivo subcutaneous implantation murine model. Upon depletion of macrophages, the subcutaneous injection of syngeneic endometrial material resulted in significant reduction in oxidative stress, endometriotic lesion size, and neovascularization. Likewise, inactivation of the lipid peroxidative gene Alox15 induced similar reduction in oxidative stress, lesion growth, and angiogenesis. Since HIF-1α is an important trigger of neoangiogenesis, we further administered a HIF-1α-specific inhibitor (PX-478) to our endometriotic model and further confirmed the same effects on the lesions. Taken together, these data suggest that an intact Alox15 pathway and HIF-1α signaling may play important roles in the macrophage-mediated oxidative stress and neovascularization of endometriosis in the early stages, suggesting anti-inflammation and antioxidation as potential therapeutic targets for the development of endometriosis.