Notch signaling controls sprouting angiogenesis of endometriotic lesions
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Angiogenesis is essential for the engraftment and growth of endometriotic lesions. In this study, we analyzed whether this process is regulated by Notch signaling. Endometriotic lesions were induced by endometrial tissue transplantation into dorsal skinfold chambers of C57BL/6 mice, which were treated with the γ-secretase inhibitor DAPT or vehicle. Vascularization, morphology, and proliferation of the newly developing lesions were analyzed using intravital fluorescence microscopy, histology, and immunohistochemistry over 14 days. Inhibition of Notch signaling by DAPT significantly increased the number of angiogenic sprouts within the endometrial grafts during the first days after transplantation when compared to vehicle-treated controls. This was associated with an accelerated vascularization, as indicated by a higher functional microvessel density of DAPT-treated lesions on day 6. However, inhibition of Notch signaling did not affect the morphology and proliferating activity of the lesions, as previously described for tumors. Both DAPT- and vehicle-treated lesions finally consisted of cyst-like dilated glands, which were surrounded by a well-vascularized stroma and contained comparable numbers of proliferating cell nuclear antigen-positive cells. These findings demonstrate that sprouting angiogenesis in endometriotic lesions is controlled by Notch signaling. However, inhibition of Notch signaling does not have beneficial therapeutic effects on lesion development.
KeywordsEndometriosis Angiogenesis Notch Tip cells Stalk cells γ-Secretase inhibitor
We are grateful for the excellent technical assistance of Janine Becker, Ruth M. Nickels, Julia Parakenings, and Sandra Schuler (Institute for Clinical and Experimental Surgery, Saarland University, Germany).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors.
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