The ovary provides a niche environment where female germ cells (or oocytes) are generated, stored within follicles and later matured in preparation for use during reproductive life. Following an extensive period of quiescence, which in human, may be up to forty years; the follicle surrounding the oocyte begins to grow, promoting maturation of the oocyte, and culminating in the expulsion of a fully mature oocyte in preparation for fertilisation. These events occur cyclically as part of the menstrual (or estrus) cycle and involve extensive remodelling of both the follicle and its surrounding extracellular tissue. Cyclic follicle activation and growth is also associated with concurrent remodelling of the blood vasculature within the ovary, specifically the vessels surrounding the growing follicle. These blood vascular remodelling changes are well explored and have been demonstrated to be necessary for follicle growth, hormone synthesis, ovulation and for the development and function of the corpus luteum. Physiologically, the lymphatic vasculature is known to closely interact with the blood vasculature and plays a number of important physiological roles including the return of extra-vascular fluid to the blood circulation, and in turn, maintenance of systemic fluid homeostasis. Additionally the lymphatic network is required for the trafficking of immune cells from the periphery to lymph nodes; during the initiation of an immune response and for the absorption of lipids and lipid soluble vitamins in the gastrointestinal tract. The lymphatic vasculature develops and functions concomitantly with the blood vasculature; however unlike the blood vasculature, the aetiology of lymphatic vasculature within the ovary is unknown. It is unclear whether lymphatic remodelling events occur in association with folliculogenesis and are necessary for fertility, as is seen with the blood vasculature. To elucidate the mechanisms involved in the establishment and remodelling of the lymphatic vasculature within the ovary, I undertook expansive characterisation of its development and hormonal regulation. I exploited both hormonal manipulation and a known model of disrupted ovarian lymphatic development, the Adamts1 null mouse line, to examine the mechanisms controlling ovarian lymphangiogenesis. Quantitative morphometric analysis of vessel size and number in postnatal mouse ovary revealed that the ovarian lymphatic vasculature develops postnatally between day 8.5 and 12.5, and in synchrony with induction of ovarian CYP19a1 (Aromatase); the time when secondary follicles become FSH-responsive and estrogenic. The establishment of the lymphatic vasculature was also associated with the induction of pro-lymphangiogenic growth factors Vegfc and Vegfd, and their receptor, Vegfr3. Formation of ovarian lymphatics required the matrix-remodelling protease Adamts1, since ovaries from Adamts1⁻/⁻ mice failed to undergo normal lymphatic vascular development. FSH promoted remodelling of the existing lymphatic vascular maturation by increasing lymphatic vessel size in normal (Adamts1⁺/⁻) ovaries, and promoted the expansion of a new lymphatic vascular network by increasing vessel number and size in Adamts1⁻/⁻ ovaries. These vessel changes were also associated with the induction of prolymphangiogenic factors, Vegfc and Vegfd, as well as their receptor, Vegfr3 providing a mechanistic explanation for the hormonal mediated lymphangiogenesis. The concurrent establishment of the lymphatic vasculature with the first postnatal induction of ovarian Aromatase, and the hormone-regulated lymphangiogenesis suggests that a hormonal communication, likely estrogen, may synchronise lymphangiogenesis with folliculogenesis. Like FSH, exogenous estradiol was able to promote the expansion of a new lymphatic vascular network by increasing vessel number and size in Adamts1⁻/⁻ ovaries. Additionally, FSH-analog eCG was able to enhance ovarian lymphangiogenesis during the window of lymphatic establishment (postnatal development of Adamts1 null), whilst inhibition of the production of estradiol using the Aromatase inhibitor Letrozole, during this same window failed to have any effect. This study is the first to investigate the relationship between ovarian lymphatic development and remodelling and folliculogenesis. The present studies reveal that the ovary undergoes lymphatic vascular remodelling, described elsewhere as adult or secondary lymphangiogenesis and that this process involves hormonal contributions from FSH and estradiol, as well as the extracellular matrix protease, Adamts1. This work provides the first evidence of a malleable lymphatic system and a model for regulation of normal adult lymphangiogenesis, and may one day be used to explore ways in which to regenerate damaged vessels to cure lymphatic diseases and disorders. These results also significantly advanced the understanding of the tightly regulated processes controlling fluid dynamics within the ovary. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1454847 / Thesis (Ph.D.) -- University of Adelaide, School of Paediatrics and Reproductive Health, 2009
| Identifer | oai:union.ndltd.org:ADTP/288346 |
| Date | January 2009 |
| Creators | Brown, Hannah Mary |
| Source Sets | Australiasian Digital Theses Program |
| Detected Language | English |
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