Three-dimensional human leiomyoma xenografts induce angiogenesis by inducing hypoxia inducible factor-1 alpha

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Authors:

Joy L. Britten, M.D., Minnie Malik, Ph.D., Carissa Pekny, M.D., Anthony DeAngelis, M.D., Ph.D., William H. Catherino, M.D., Ph.D. 

Abstract:

Objective

To characterize the method by which angiogenesis occurred in three-dimensional (3D) leiomyoma xenografts, and to assess the impact of hypoxia on two-dimensional (2D) and 3D myometrial and leiomyoma cells and leiomyoma xenografts in vivo.


Design

Laboratory study.


Setting

Academic research.


Patient(s)

Cell cultures from patient-matched myometrial and leiomyoma tissues.


Intervention(s)

In vivo 3D leiomyoma xenografts from ovariectomized mice treated with gonadal hormones; myometrial and leiomyoma cells in 2D and 3D growth formats exposed to 1% oxygen.


Main Outcome Measure(s)

Protein expression.


Result(s)

Blood vessels in the xenograft estradiol group are identified with anti-mouse/anti-rat CD31/PECAM-1 antibody. Hormone-stimulated 3D leiomyoma xenografts stain positively for adrenomedullin (ADM). Myometrial cells exposed to 1% oxygen demonstrated an increase in hypoxia-inducible factor (HIF)-1α at 6 hours and a marked increase at 24 hours. Under normoxic conditions, leiomyoma cells at 6 hours show increased expression of HIF-1α, which is further increased at 24 hours. Leiomyoma cells under hypoxia demonstrated a 1.14-fold decrease in HIF-1α expression at 6 hours and no change at 24 hours. Hypoxic myometrium decreased the proangiogenic protein ADM expression at 6 hours and showed a >1.5-fold increase at 24 hours. Normoxic leiomyoma decrease ADM at 24 hours and showed a >1.5-fold increase at 24 hours of hypoxia.


Conclusion(s)

Hypoxia-induced HIF-1α expression facilitates angiogenesis in 3D xenografts in vivo by increasing the expression of the proangiogenic protein ADM. Angiogenesis contributes to the viability and extended survival of these xenografts. Furthermore, 2D myometrial and leiomyoma cells increase HIF-1α and ADM expression in vitro under hypoxic conditions.

Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders. The journal publishes juried original scientific articles in clinical and laboratory research relevant to reproductive endocrinology, urology, andrology, physiology, immunology, genetics, contraception, and menopause. Fertility and Sterility® encourages and supports meaningful basic and clinical research, and facilitates and promotes excellence in professional education, in the field of reproductive medicine.

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