Degree

Doctor of Philosophy (PhD)

Department

Veterinary Clinical Sciences

Document Type

Dissertation

Abstract

Kisspeptins, a family of small peptides derived from the Kiss1 gene, have been described in trophoblast cell dynamics, placentation, and pregnancy outcomes. Furthermore, many other physiological functions have been attributed to kisspeptins, including neuroendocrine regulation of puberty and cyclicity, and peripheral and central regulation of metabolism and adipogenesis. Herein, studies were performed in the Blood Pressure High Subline 5 (BPH/5) mouse and the horse to further investigate the role of kisspeptins in pregnancy. The BPH/5 mouse recapitulates the main features of human preeclampsia (PE), a hypertensive disorder of pregnancy associated with maternal and fetal adverse outcomes. BPH/5 phenotypic characteristics include sexually dimorphic obesity, abnormal estrous cycles, and defective placentation, all of which have been linked to kisspeptin signaling. Therefore, I aimed to characterize spatiotemporal Kiss1 expression, upstream and downstream genes in the BPH/5 uterus and at the maternal-fetal interface. Synchronization of sex steroid hormones (SSH), regulators of uterine Kiss1, normalized BPH/5 uteroplacental expression of estrogen receptor alpha, progesterone receptor, Kiss1, and downstream molecules as well as improved ultrasonographic and histological signs of placentation. I further investigated the metabolic profile and pubertal development of offspring born to obese preeclamptic-like BPH/5 dams. In agreement with the role of kisspeptins in adipogenesis, sexually dimorphic adipose tissue Kiss1 was observed in the BPH/5 mouse, which was associated with abnormal circulating leptin and alterations in pubertal development. BPH/5 maternal weight loss restored SSH levels and adipose tissue Kiss1. Altogether, the findings provide groundwork for further studies using the BPH/5 mouse to elucidate the transgenerational importance of kisspeptin regulation in obesity and PE. While the role of kisspeptins in human pregnancy continues, the significance of these peptides in equine pregnancy remains vastly unexplored. Therefore, I aimed to investigate Kiss1 expression and the effects of Kiss1-derived kisspeptin-10 on proliferation and migration of equine chorionic girdle trophoblast cells. Physiologic concentrations of equine kisspeptin-10 did not affect chorionic girdle trophoblast cell migration in two different assays. In summary, the aforementioned mechanistic studies provide evidence of placental and adipose tissue kisspeptin dysregulation in a mouse model of PE. Further, these studies shed light on species-specific differences in kisspeptin signaling.

Date

11-3-2022

Committee Chair

Sones, Jennifer

Available for download on Sunday, November 02, 2025

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