Abstract
Endometriosis is a frequent gynecological disease that is characterized by the development of vascularized endometriotic lesions inside the peritoneal cavity. Herein, we analyzed whether circulating endothelial progenitor cells (EPCs) are recruited and incorporated into the microvasculature of these lesions. Intraperitoneal endometriotic lesions were surgically induced in irradiated FVB/N mice, which were reconstituted with bone marrow from FVB/N-TgN (Tie2/green fluorescent protein [GFP]) 287 Sato mice. Vascularization and recruitment of GFP-positive EPCs in the lesions was analyzed by intravital fluorescence microscopy and immunohistochemistry over 4 weeks. The numbers of stem cell antigen-1 (Sca-1)/vascular endothelial growth factor receptor-2-positive EPCs in blood and hematopoietic organs of additional endometriotic and control mice were assessed by flow cytometry. We found that approximately 15% of the microvascular endothelium in engrafting endometriotic lesions consisted of incorporated GFP-positive EPCs. Recruitment of EPCs into the lesions coincided with the establishment of own blood supply and the expression of stromal cell-derived factor-1. Accordingly, treatment with the stromal cell-derived factor-1/chemokine receptor type 4 axis antagonist AMD3100 significantly decreased the number of recruited EPCs and the vascularization of endometriotic lesions. However, endometriosis did not induce increased levels of EPCs in the blood, bone marrow, and spleen of C57BL/6 mice. To our knowledge, our findings indicate for the first time that vasculogenesis (ie, de novo generation of blood vessels from EPCs) may represent an integral mechanism in the pathogenesis of endometriosis.