Control of ovarian vascular remodeling by CCAAT/enhancer binding proteins alpha and beta

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PROJECT SUMMARY/ABSTRACT Infertility occurs in approximately 15% of women of reproductive age in the United States. Approximately half of the cases involve impaired ovulation, the cause of which is often elusive. The aim of this project is to achieve new understanding of ovulatory defects that will serve as a foundation for effective treatment of infertility. It is known that obesity negatively impacts female fertility and ovulation, but the underlying mechanism remains to be elucidated. Recent findings highlight the crucial role of preovulatory ovarian vascular remodeling in successful ovulation: the ovulatory luteinizing hormone (LH) surge induces a series of vascular remodeling processes in the ovary, including changes in vascular permeability, vessel contraction and formation of new blood vessels. CCAAT/enhancer binding proteins alpha and beta (C/EBPα and C/EBPβ, jointly abbreviated C/EBPα/β) are rapidly induced in granulosa cells by the LH surge and function as important regulators of ovulation. Based on our preliminary data, which show the profound effects of C/EBPα/β deficiency on ovarian vascular remodeling in mice, we hypothesize that C/EBPα and C/EBPβ are key mediators by which the LH surge controls vascular remodeling in preovulatory ovaries. Given obesity’s negative impact on vascular function in general and on ovarian blood flow in women in particular, we also propose the novel concept that ovarian vascular remodeling is a key mediator between obesity and ovulation failure. This proposal first seeks to use murine models of ovulation failure and disrupted ovarian vascular remodeling to identify their regulatory mechanisms downstream of the LH surge, then addresses the knowledge deficit around obesity’s impact on ovarian vasculature. To achieve these goals we will apply 3-dimensional quantitative intravital imaging to a transgenic mouse line with ovary-specific ablation of C/EBPα/β to first define the specific vascular remodeling events regulated by C/EBPα/β in preovulatory ovaries, then determine in a diet-induced obese mouse model the impact of obesity on the activity of C/EBPα/β and vascular remodeling during ovulation. We will further seek understanding of cell type-specific mechanisms regulating preovulatory vascular remodeling and ovulation using single-cell, next-generation sequencing technologies; these approaches will also reveal whether epigenetic mechanisms regulating chromatin accessibility play a key role in preovulatory vascular remodeling and ovulation, and whether C/EBPα/β mediate this interaction. Successful completion of the proposed studies will advance our understanding of ovulation regulation and have a major impact by elucidating links among obesity, epigenetic regulation, and ovarian function, thus enabling improved treatment of many cases of female infertility.