Enhancement of neoangiogenesis and follicle survival by sphingosine-1-phosphate in human ovarian tissue xenotransplants

PLoS One. 2011 Apr 29;6(4):e19475. doi: 10.1371/journal.pone.0019475.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Cryopreservation
  • Female
  • Fingolimod Hydrochloride
  • Graft Survival
  • Humans
  • Immunohistochemistry / methods
  • Immunosuppressive Agents / pharmacology
  • Lysophospholipids / metabolism
  • Mice
  • Mice, SCID
  • Neovascularization, Physiologic*
  • Ovarian Follicle / physiology*
  • Ovary / blood supply*
  • Ovary / transplantation*
  • Oxadiazoles / pharmacology
  • Propylene Glycols / pharmacology
  • Sphingosine / analogs & derivatives
  • Sphingosine / metabolism
  • Sphingosine / pharmacology
  • Thiophenes / pharmacology
  • Transplantation, Heterologous

Substances

  • Immunosuppressive Agents
  • Lysophospholipids
  • Oxadiazoles
  • Propylene Glycols
  • SEW2871
  • Thiophenes
  • sphingosine 1-phosphate
  • Fingolimod Hydrochloride
  • Sphingosine