Local intra-uterine Ang-(1-7) infusion attenuates PGE2 and 6-keto PGF1α in decidualized uterus of pseudopregnant rats

Background: Cyclooxygenase (COX)-derived prostanoids (PGE2, PGI2) are important contributors to the process of decidualization. Previous studies showed the presence of Ang-(1-7) in the primary and secondary decidualized zones of the implantation site at early pregnancy. Decreased concentrations of Ang-(1-7) were found in the decidualized uterus compared to the non-decidualized uterus of pseudopregnant rats, suggesting that low levels of Ang-(1-7) are required for successful decidualization at early pregnancy. Methods: To understand the role of Ang-(1-7) in prostaglandin production in a decidualized uterus, induced by a bolus injection of sesame oil, Ang-(1-7) (24 μg/kg/h) or vehicle was then infused directly into the decidualized uterine horn using an osmotic minipump. The right horns were not injected or infused and served as nondecidualized uterine horns in both groups of animals. Results: Decidualization increased PGE2 concentration in the uterus (0.53±0.05 vs. 12.0±3.2 pmol/mg protein, p\u3c0.001, non-decidualized vs. decidualized horns); Ang-(1-7) infusion attenuated the increase of PGE2 (12.0± 3.2 vs. 5.1±1.3 pmol/mg protein, p\u3c0.01 control vs. Ang-(1-7) treated decidualized horns). The stable metabolite of PGI2 (6-keto PGF1α) was increased with decidualization (0.79±0.17 vs. 3.5±0.82 pmol/mg protein, p\u3c0.001, non-decidualized vs. decidualized horns). Ang-(1-7) infusion attenuated the increase in 6keto PGF1α in the decidualized horn (3.5±0.82 vs 1.8±0.37 pmol/mg protein, p\u3c0.05 control vs. Ang-(1-7) treated decidualized horns). The circulating levels of 6-keto-PGF1a and TXB2 were decreased by Ang-(1-7) infusion, while no difference was observed in circulating PGE2. Although the global assessment of cleaved caspase 3 immunostaining, a marker of apoptosis, was unchanged within the Ang-(1-7) decidualized horn, there were localized decreases in cleaved caspase 3 staining in the luminal region in the decidualized uterus of Ang-(1-7)-treated rats. Conclusions: These studies show that increased local uterine Ang-(1-7) alters the uterine prostaglandin environment, possibly leading to disruptions of early events of decidualization

Local uterine Ang-(1-7) infusion augments the expression of cannabinoid receptors and differentially alters endocannabinoid metabolizing enzymes in the decidualized uterus of pseudopregnant rats

Background Endocannabinoids (ECs) are important contributors to implantation and decidualization and are suppressed in early pregnancy. Elevated levels of anandamide (AEA), the endogenous ligand for the CB1 and CB2 receptors (R), interfere with receptivity of the blastocyst. Ang-(1–7) is down-regulated in the implantation site (IS) in normal pregnancy at day 7 of gestation. We determined the effects of intra-uterine angiotensin-(1–7) [Ang-(1–7)] (24 microg/kg/h) or vehicle given into the left uterine horn on the ECs in the decidualized uterus. Methods Ovariectomized rats were sensitized for the decidual cell reaction by steroid treatment and decidualization was induced by a bolus of oil injected into the left horn; the right horn served as a control. Results Decidualization increased endometrial permeability (3.1+/−0.2 vs. 7.1+/−0.5 uterus/muscle of cpm of (125)I-BSA, p \u3c 0.0001). VEGF mRNA was increased by the decidualization (1.4-fold, p \u3c 0.05) and by Ang-(1–7) (2.0-fold, p \u3c 0.001). CB1R mRNA was reduced by decidualization (2.7-fold, p \u3c 0.001), but increased by Ang-(1–7) (1.9-fold, p \u3c 0.05). CB2R mRNA was increased by decidualization (4-fold, p \u3c 0.05) and by Ang-(1–7) (2.4-fold, p \u3c 0.001). The enzyme metabolizing AEA, fatty acid amide hydrolase (FAAH), was reduced by decidualization (7.8 fold, p \u3c 0.001) and unchanged by Ang-(1–7) (p \u3e 0.05), whereas the enzyme metabolizing 2-arachidonoylglycerol, monoacyl glycerol lipase (MAGL), was unchanged by decidualization (p \u3e 0.05) and increased by Ang-(1–7) (1.7 fold, p \u3c 0.001). Conclusions These findings report for the first time that Ang-(1–7) augments the expression of CB1R, CB2R and MAGL in the decidualized uterus and thus may interfere with the early events of decidualization

Systemic outcomes of (Pyr(1))-apelin-13 infusion at mid-late pregnancy in a rat model with preeclamptic features

Preeclampsia is a syndrome with diverse clinical presentation that currently has no cure. The apelin receptor system is a pleiotropic pathway with a potential for therapeutic targeting in preeclampsia. We established the systemic outcomes of (Pyr(1))-apelin-13 administration in rats with preeclamptic features (TGA-PE, female transgenic for human angiotensinogen mated to male transgenic for human renin). (Pyr(1))-apelin-13 (2 mg/kg/day) or saline was infused in TGA-PE rats via osmotic minipumps starting at day 13 of gestation (GD). At GD20, TGA-PE rats had higher blood pressure, proteinuria, lower maternal and pup weights, lower pup number, renal injury, and a larger heart compared to a control group (pregnant Sprague-Dawley rats administered vehicle). (Pyr(1))-apelin-13 did not affect maternal or fetal weights in TGA-PE. The administration of (Pyr(1))-apelin-13 reduced blood pressure, and normalized heart rate variability and baroreflex sensitivity in TGA-PE rats compared to controls. (Pyr(1))-apelin-13 increased ejection fraction in TGA-PE rats. (Pyr(1))-apelin-13 normalized proteinuria in association with lower renal cortical collagen deposition, improved renal pathology and lower immunostaining of oxidative stress markers (4-HNE and NOX-4) in TGA-PE. This study demonstrates improved hemodynamic responses and renal injury without fetal toxicity following apelin administration suggesting a role for apelin in the regulation of maternal outcomes in preeclampsia

Plasma ACE2 predicts outcome of COVID-19 in hospitalized patients

AimsSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to angiotensin converting enzyme 2 (ACE2) enabling entrance of the virus into cells and causing the infection termed coronavirus disease of 2019 (COVID-19). Here, we investigate associations between plasma ACE2 and outcome of COVID-19.Methods and resultsThis analysis used data from a large longitudinal study of 306 COVID-19 positive patients and 78 COVID-19 negative patients (MGH Emergency Department COVID-19 Cohort). Comprehensive clinical data were collected on this cohort, including 28-day outcomes. The samples were run on the Olink® Explore 1536 platform which includes measurement of the ACE2 protein. High admission plasma ACE2 in COVID-19 patients was associated with increased maximal illness severity within 28 days with OR = 1.8, 95%-CI: 1.4-2.3 (P ConclusionThis study suggests that measuring plasma ACE2 is potentially valuable in predicting COVID-19 outcomes. Further, ACE2 could be a link between COVID-19 illness severity and its established risk factors hypertension, pre-existing heart disease and pre-existing kidney disease

Local uterine Ang-(1–7) infusion augments the expression of cannabinoid receptors and differentially alters endocannabinoid metabolizing enzymes in the decidualized uterus of pseudopregnant rats

Background Endocannabinoids (ECs) are important contributors to implantation and decidualization and are suppressed in early pregnancy. Elevated levels of anandamide (AEA), the endogenous ligand for the CB1 and CB2 receptors (R), interfere with receptivity of the blastocyst. Ang-(1–7) is down-regulated in the implantation site (IS) in normal pregnancy at day 7 of gestation. We determined the effects of intra-uterine angiotensin-(1–7) [Ang-(1–7)] (24 microg/kg/h) or vehicle given into the left uterine horn on the ECs in the decidualized uterus. Methods Ovariectomized rats were sensitized for the decidual cell reaction by steroid treatment and decidualization was induced by a bolus of oil injected into the left horn; the right horn served as a control. Results Decidualization increased endometrial permeability (3.1+/−0.2 vs. 7.1+/−0.5 uterus/muscle of cpm of (125)I-BSA, p \u3c 0.0001). VEGF mRNA was increased by the decidualization (1.4-fold, p \u3c 0.05) and by Ang-(1–7) (2.0-fold, p \u3c 0.001). CB1R mRNA was reduced by decidualization (2.7-fold, p \u3c 0.001), but increased by Ang-(1–7) (1.9-fold, p \u3c 0.05). CB2R mRNA was increased by decidualization (4-fold, p \u3c 0.05) and by Ang-(1–7) (2.4-fold, p \u3c 0.001). The enzyme metabolizing AEA, fatty acid amide hydrolase (FAAH), was reduced by decidualization (7.8 fold, p \u3c 0.001) and unchanged by Ang-(1–7) (p \u3e 0.05), whereas the enzyme metabolizing 2-arachidonoylglycerol, monoacyl glycerol lipase (MAGL), was unchanged by decidualization (p \u3e 0.05) and increased by Ang-(1–7) (1.7 fold, p \u3c 0.001). Conclusions These findings report for the first time that Ang-(1–7) augments the expression of CB1R, CB2R and MAGL in the decidualized uterus and thus may interfere with the early events of decidualization