Abstract
Preeclampsia is a multifaceted pregnancy-associated hypertensive disorder that poses a major threat to maternal and fetal health. Though the etiology is not fully understood, syncytiotrophoblast stress is postulated to be a major driver of maternal symptomology. We previously demonstrated that regulator of G protein signaling-2 (RGS2) expression decreases in human preeclamptic placenta and has a transcriptional dependence on histone deacetylase 9 (HDAC9) in trophoblast cells. Furthermore, experimental reductions of Rgs2 expression in the mouse fetoplacental unit are sufficient to induce preeclampsia-like features, including placental stress, in C57BL/6J dams. Here, we examined the hypotheses that HDAC9 and RGS2 are both expressed within syncytiotrophoblasts, that HDAC9 and RGS2 expression are positively correlated within these cells, and that expression of each is reduced within syncytiotrophoblasts during preeclampsia. HDAC9 and RGS2 mRNA were localized and quantified in syncytiotrophoblast cells of human placental samples from pregnancies with and without preeclampsia, using laser-capture microdissection and in situ hybridization methods. Expression of Hdac9 and Rgs2 was similarly localized in the syncytiotrophoblast of the mouse placenta. Throughout, HDAC9/Hdac9 and RGS2/Rgs2 were detected and positively correlated in syncytiotrophoblasts, but expression of each was substantially reduced during preeclampsia. These results document reduced HDAC9 and RGS2 expression specifically in syncytiotrophoblast cells during preeclampsia and provide additional correlative support of HDAC9-mediated control of RGS2 expression within this population of trophoblasts. This work provides rationale to further explore cell-specific disruptions in HDAC9 and RGS2 control and function as a cause of syncytiotrophoblast stress and ultimately preeclampsia.NEW & NOTEWORTHY Syncytiotrophoblast stress contributes to the pathogenesis of preeclampsia, but many of the underlying causes remain undetermined. Previous work has implicated the loss of placental HDAC9-mediated Rgs2 transcription in the disorder. Extending these findings, we report that HDAC9 and RGS2 were abundant and localized primarily to syncytiotrophoblast cells of the control placenta. Expression of both targets was attenuated in these cells during preeclampsia and thus may be an underappreciated source of syncytiotrophoblast stress, warranting further investigation.