Abstract
Limited evidence suggests that the sphingosine-1-phosphate/sphingosine kinase 1 (S1P/SPHK1) signalling pathway is involved in the pathogenesis of endometriosis. Therefore, we analyzed in this study whether the inhibition of SPHK1 and, consequently, decreased levels of S1P affected the vascularization and growth of endometriotic lesions. Endometriotic lesions were surgically induced in the peritoneal cavity and the dorsal skinfold chamber of female BALB/c mice. The animals received a daily dose of the SPHK1 inhibitor SKI-5C or vehicle (control). Analyses involved the determination of lesion growth, cyst formation, microvessel density and cell proliferation within peritoneal endometriotic lesions by means of high-resolution ultrasound imaging, caliper measurement, histology and immunohistochemistry. In the dorsal skinfold chamber model the development of newly formed microvascular networks and their microhemodynamic parameters within endometriotic lesions were investigated by means of intravital fluorescence microscopy. SKI-5C significantly inhibited the development and vascularization of peritoneal endometriotic lesions, as indicated by a reduced growth and cyst formation, a lower microvessel density and a suppressed cell proliferation, when compared to vehicle-treated controls. Endometriotic lesions in dorsal skinfold chambers of SKI-5C-treated animals exhibited a significantly smaller lesion size, lower functional microvessel density, smaller microvessel diameters and a reduced blood perfusion of the newly developing microvascular networks. SPHK1/S1P signalling promotes the establishment and progression of endometriotic lesions. The inhibition of this pathway suppresses the development of endometriotic lesions, suggesting SPHK1 as a potential novel target for future endometriosis therapy.
Highlights
As a widespread and common disease, endometriosis affects about 5%–10% of women during their reproductive years
An increasing number of studies suggests that sphingolipids, such as S1P, are involved in the pathogenesis of endometriosis
S1P promotes the growth of endometriotic cells through the overexpression of IL-6 a pro-inflammatory cytokine associated with the establishment of endometriotic lesions (Bergqvist et al, 2001)
Summary
As a widespread and common disease, endometriosis affects about 5%–10% of women during their reproductive years. Santulli and co-workers demonstrated that the expression of S1P receptors and enzymes of the S1P pathway, such as SPHK1, are deregulated in the endometrium and endometriotic tissue of endometriosis patients (Santulli et al, 2012). Based on these findings, we analyzed in the present. The sphingosine kinase-1 inhibitor SKI-5C suppresses the development of endometriotic lesions. Inhibition of sphingosine kinase-1signalling reduces the formation of new microvascular networks. Study whether the targeting of SPHK1 with the specific inhibitor SKI5C affects the development and vascularization of endometriotic lesions in two different mouse models of the disease
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