Reduced mRNA Expression of RGS2 (Regulator of G Protein Signaling-2) in the Placenta Is Associated With Human Preeclampsia and Sufficient to Cause Features of the Disorder in Mice.

Cascade-specific termination of G protein signaling is catalyzed by the RGS (regulator of G protein signaling) family members, including . Angiotensin, vasopressin, and endothelin are implicated in preeclampsia, and is known to inhibit G protein cascades activated by these hormones. Mutations in are associated with human hypertension and increased risk of developing preeclampsia and its sequelae. RGS family members are known to influence maternal vascular function, but the role of within the placenta has not been explored. Here, we hypothesized that reduced expression of within the placenta represents a risk factor for the development of preeclampsia. Although cAMP/CREB signaling was enriched in placentas from human pregnancies affected by preeclampsia compared with clinically matched controls and is known to be a CREB-responsive gene, mRNA was reduced in placentas from pregnancies affected by preeclampsia. Experimentally reducing expression within the feto-placental unit was sufficient to induce preeclampsia-like phenotypes in pregnant wild-type C57BL/6J mice. Stimulation of transcription within immortalized human HTR8/SVneo trophoblasts by cAMP/CREB signaling was discovered to be dependent on the activity of histone deacetylase activity, and more specifically, HDAC9 (histone deacetylase-9), and expression was reduced in placentas from human pregnancies affected by preeclampsia. We conclude that reduced expression of within the placenta may mechanistically contribute to preeclampsia. More generally, this work identifies as an -dependent CREB-responsive gene, which may contribute to reduced expression in placenta during preeclampsia.