Dysregulated Kisspeptin/Receptor Expression at the Maternal-Fetal Interface in the Preeclamptic-like BPH/5 Mouse

Preeclampsia (PE) is a hypertensive pregnancy syndrome estimated to cause the death of approximately 63,000 women worldwide annually. Insufficient invasion of extravillous trophoblast cells (EVT) into the maternal decidua and inadequate placentation are key adverse events in the pathogenesis of PE. Kisspeptins (KP), a family of small peptides derived from the kiss1 gene product, have been implicated as physiologic inhibitors of EVT invasion, a mechanism associated with upregulation of Tissue Inhibitor of Metalloproteinases (TIMP) and downregulation of Matrix Metalloproteinases (MMP). In PE, placental dysregulation of kiss1 and the KP receptor (kiss1r) have been proposed. Based on in vitro studies and evaluation of term PE placentas, it has been suggested that kiss1 and kiss1r mRNA are overexpressed at the maternal‐fetal interface during early gestation and excessively impair EVT invasion. However, the innate challenges involving human sample collection and early diagnosis of PE prevent a holistic understanding of KP role. Therefore, the objective of this study was to utilize the preeclamptic‐like BPH/5 mouse to investigate uteroplacental KP dysregulation throughout gestation. We have previously shown that pregnant BPH/5 females spontaneously develop poor placentation with decreased trophoblast invasion and inadequately remodeled decidual vessels. Hence, we hypothesized that uteroplacental expression of kiss1/kiss1r would be temporally dysregulated in the BPH/5 compared to the control C57 mice. Furthermore, we hypothesized that higher kiss1/kiss1r levels would be associated with upregulation of TIMP2, an important endogenous inhibitor of MMPs and cellular migration. To test our hypothesis, implantation sites and placentas of BPH/5 and C57 mice were collected at the embryonic days (e) 4.5, 7.5, 12.5, 14.5 and 18.5. The kiss1, kiss1r and TIMP2 mRNA levels were measured using RT‐PCR and comparisons were performed using unpaired t‐test. A similar expression pattern of kiss1 and kiss1r was seen throughout gestation in BPH/5 and control groups, with levels increasing from early (e4.5) to mid‐gestation (e14.5) and decreasing thereafter (e14.5 and e18.5). During the peak of decidualization (e7.5), BPH/5 mice presented 2‐fold higher kiss1 and kiss1r compared to C57 mice (n = 6; p ≤ 0. 05). In accordance with the proposed KP role, a 10‐fold increase in TIMP2 was also seen in BPH/5 mice at e7.5 (n = 6, p ≤ 0.05). In mid‐gestation (e14.5) kiss1r levels were 2‐fold lower in BPH/5 (n = 5) than in C57 (n = 6; p < 0.05), whereas kiss1 levels were not different among groups (n = 6; p > 0.05). In late gestation (e18.5), kiss1 and kiss1r were 3‐ and 2.5‐fold lower respectively in placentas of BPH/5 mice (n = 6; p ≤ 0.05). To the author’s knowledge, this is the first report of translational studies using an animal model of PE to investigate the role of KP in PE‐associated poor placental development. A kiss1/kiss1r dysregulation is reported, with higher expression levels in the preeclamptic‐like mouse in the peak of decidualization, and concurrent upregulation of TIMP2. Further studies are needed to investigate KP‐related upstream and downstream signaling pathways in the context of PE.