Abstract
Optimal distribution of heterogeneous organelles and cell types within an organ is essential for physiological processes. Unique for the ovary, hormonally regulated folliculogenesis, ovulation, luteal formation/regression and associated vasculature changes lead to tissue remodeling during each reproductive cycle. Using the CLARITY approach and marker immunostaining, we identified individual follicles and corpora lutea in intact ovaries. Monitoring lifetime changes in follicle populations showed age-dependent decreases in total follicles and percentages of advanced follicles. Follicle development from primordial to preovulatory stage was characterized by 3 × 105-fold increases in volume, decreases in roundness, and decreased clustering of same stage follicles. Construction of follicle-vasculature relationship maps indicated age- and gonadotropin-dependent increases in vasculature and branching surrounding follicles. Heterozygous mutant mice with deletion of hypoxia-response element in the vascular endothelial growth factor A (VEGFA) promoter showed defective ovarian vasculature and decreased ovulatory responses. Unilateral intrabursal injection of axitinib, an inhibitor of VEGF receptors, retarded neo-angiogenesis that was associated with defective ovulation in treated ovaries. Our approach uncovers unique features of ovarian architecture and essential roles of vasculature in organizing follicles to allow future studies on normal and diseased human ovaries. Similar approaches could also reveal roles of neo-angiogenesis during embryonic development and tumorigenesis.
Highlights
Optimal distribution of heterogeneous organelles and cell types within an organ is essential for physiological processes
Massive atresia, and rupture as well as luteal formation/regression are hormonally regulated and associated with neo-angiogenesis that is rarely found in adult mammals[4]
In addition to their unique homogenous texture, corpora lutea showed staining for VEGF important for angiogenesis[8]
Summary
Optimal distribution of heterogeneous organelles and cell types within an organ is essential for physiological processes. Unique for the ovary, hormonally regulated folliculogenesis, ovulation, luteal formation/regression and associated vasculature changes lead to tissue remodeling during each reproductive cycle. Among ~20 early antral follicles present during early follicular phase of the menstrual cycle in women, most become atretic and only one reaches antral/preovulatory stages This dominant follicle secrets a majority of circulating sex steroids necessary for maintaining reproductive cyclicity and eventually ovulates a mature oocyte capable of developing into a new life[2,3]. Using specific markers and advanced computer algorithms, we imaged ovarian follicles and corpora lutea in intact ovaries and generated 3D digital maps of ovarian organelles in relation to vasculatures to reveal changes in follicle sizes, location, roundness, clustering, interrelationships, and vasculature throughout reproductive life. The purpose of the current study was to use the CLARITY approach to elucidate folliculogenesis and the relationship between vasculature and follicles in mice after birth to adult life
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