title: Enhancement of neoangiogenesis and follicle survival by sphingosine-1-phosphate in human ovarian tissue xenotransplants.
abstract: Ovarian transplantation is one of the key approaches to restoring fertility in women who became menopausal as a result of cancer treatments. A major limitation of human ovarian transplants is massive follicular loss during revascularization. Here we investigated whether sphingosine-1-phosphate or its receptor agonists could enhance neoangiogenesis and follicle survival in ovarian transplants in a xenograft model. Human ovarian tissue xenografts in severe-combined-immunodeficient mice were treated with sphingosine-1-phosphate, its analogs, or vehicle for 1-10 days. We found that sphingosine-1-phosphate treatment increased vascular density in ovarian transplants significantly whereas FTY720 and SEW2871 had the opposite effect. In addition, sphingosine-1-phosphate accelerated the angiogenic process compared to vehicle-treated controls. Furthermore, sphingosine-1-phosphate treatment was associated with a significant proliferation of ovarian stromal cell as well as reduced necrosis and tissue hypoxia compared to the vehicle-treated controls. This resulted in a significantly lower percentage of apoptotic follicles in sphingosine-1-phosphate-treated transplants. We conclude that while sphingosine-1-phosphate promotes neoangiogenesis in ovarian transplants and reduces ischemic reperfusion injury, sphingosine-1-phosphate receptor agonists appear to functionally antagonize this process. Sphingosine-1-phosphate holds great promise to clinically enhance the survival and longevity of human autologous ovarian transplants.
authors.affiliation: Laboratory of Molecular Reproduction, Institute for Fertility Preservation, Department of Obstetrics and Gynecology, New York Medical College, Valhalla, New York, United States of America.
authors.forename: Reza
authors.initials: R
authors.lastname: Soleimani
authors.forename: Elke
authors.initials: E
authors.lastname: Heytens
authors.forename: Kutluk
authors.initials: K
authors.lastname: Oktay
mesh_terms: D000818:Animals; D017209:Apoptosis; D015925:Cryopreservation; D005260:Female; D000068876:Fingolimod Hydrochloride; D006085:Graft Survival; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D018919:Neovascularization, Physiologic; D006080:Ovarian Follicle / Q000502:physiology*; D010053:Ovary / Q000098:blood supply* / Q000637:transplantation*; D010069:Oxadiazoles / Q000494:pharmacology; D011409:Propylene Glycols / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014183:Transplantation, Heterologous
chemical_list: D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D010069:Oxadiazoles; D011409:Propylene Glycols; C503964:SEW2871; D013876:Thiophenes; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine