Targeting sphingosine kinase‐1 with the low MW inhibitor SKI‐5C suppresses the development of endometriotic lesions in mice

Jeannette Rudzitis-Auth, Jeannette Rudzitis‐Auth, Anika Christoffel, Michael D Menger, Matthias W. Laschke
British journal of pharmacology · 2021 · vol. 178(20) , pp. 4104–4118 · doi:10.1111/bph.15601 · PMID:34185874 · W3173610760
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Inhibition of sphingosine kinase 1 with SKI-5C reduced endometriotic lesion growth, vascularization, and proliferation in mice.

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Abstract

BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSIONS AND IMPLICATIONS: 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.

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Condition tags

mesh:D004715endometriosis

MeSH descriptors

Endometriosis Endometriosis Animals Female Humans Mice Mice, Inbred BALB C Neovascularization, Pathologic Neovascularization, Pathologic Phosphotransferases (Alcohol Group Acceptor) Sphingosine Sphingosine Kinase

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