Requirement for ADAMTS-1 in extracellular matrix remodeling during ovarian folliculogenesis and lymphangiogenesis

Abstract

Murine ovarian folliculogenesis commences after birth involving oocyte growth, somatic cell differentiation and structural remodeling of follicle stromal boundaries. The extracellular metalloproteinase ADAMTS-1 has activity against proteoglycans and collagen and is produced by the granulosa cells of ovarian follicles. Mice with ADAMTS-1 gene disruption are subfertile due to an unknown mechanism resulting in severely reduced ovulation. Here we show that ADAMTS-1 is necessary for structural remodeling during ovarian follicle growth. A significant reduction in the number of healthy growing follicles and corresponding follicle dysmorphogenesis commencing at the stage of antrum formation was identified in ADAMTS-1-/- ovaries. Morphological analysis and immunostaining of basement membrane components identified stages of follicle dysgenesis from focal disruption in ECM integrity to complete loss of follicular structures. Cells expressing the thecal marker Cyp-17 were lost from dysgenic regions, while oocytes and dispersed cells expressing the granulosa cell marker anti-mullerian hormone persisted in ovarian stroma. Furthermore, we found that the ovarian lymphatic system develops coincidentally with follicular development in early postnatal life but is severely delayed in ADAMTS-1-/- ovaries. These novel roles for ADAMTS-1 in structural maintenance of follicular basement membranes and lymphangiogenesis provide new mechanistic understanding of folliculogenesis, fertility and disease.