Preeclampsia, a major cause of maternal and perinatal mortality and morbidity, is thought to be attributed, in part, to impaired trophoblast invasion. Peroxisome proliferator-activated receptors are ligand-activated transcription factors expressed in trophoblasts, which regulate the expression of a number of genes involved in cell differentiation and proliferation. We investigated the effect of the administration of a peroxisome proliferator-activated receptor-γ antagonist during uncomplicated pregnancy in rats. Using an intraperitoneal miniosmotic pump, healthy pregnant rats were administered either vehicle or the peroxisome proliferator-activated receptor-γ–specific antagonist, T0070907 (1 mg/kg per day from gestational days 11–15). Rats treated with T0070907 developed key features of preeclampsia, including elevated mean arterial blood pressure, proteinuria, endothelial dysfunction, reduced pup weight, and increased platelet aggregation. T0070907-treated rats had reduced plasma vascular endothelial growth factor and increased plasma soluble fms-like tyrosine kinase 1. Furthermore, increases in total placental soluble fms-like tyrosine kinase 1 mRNA and fms-like tyrosine kinase 1 protein were also demonstrated, suggesting the placenta as the main contributor to the increased circulating levels of soluble fms-like tyrosine kinase 1. The labyrinthine trophoblast in the placentas of T0070907-treated rats were less differentiated, had increased cellular proliferation, and were strongly immunopositive for CD-31 staining, indicating adaptive angiogenesis. The present study suggests that peroxisome proliferator-activated receptor-γ may play a pivotal role in the progression of a healthy pregnancy and may critically regulate the risk of preeclampsia. These findings have important implications regarding the underlying etiology of preeclampsia and potential therapeutic targets.

Preeclampsia is a multisystemic disorder of pregnancy characterized by hypertension, proteinuria, and maternal endothelial dysfunction. It is a major cause of maternal and perinatal morbidity and mortality and is thought to be attributable, in part, to inadequate trophoblast invasion. Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-activated transcription factor expressed in trophoblasts, and the vasculature of which activation has been shown to improve endothelium-dependent vasodilatation in hypertensive conditions. We investigated the effects of the administration of a PPAR-γ agonist using the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. The selective PPAR-γ agonist, rosiglitazone, was administered to pregnant rats that had undergone RUPP surgery. To investigate whether any observed beneficial effects of PPAR-γ activation were mediated by the antioxidant enzyme, heme oxygenase 1, rosiglitazone was administered in combination with the heme oxygenase 1 inhibitor tin-protoporphyrin IX. RUPP rats were characterized by hypertension, endothelial dysfunction, and elevated microalbumin:creatinine ratios. Rosiglitazone administration ameliorated hypertension, improved vascular function, and reduced the elevated microalbumin:creatinine ratio in RUPP rats. With the exception of microalbumin:creatinine ratio, these beneficial effects were abrogated in the presence of the heme oxygenase 1 inhibitor. Administration of a PPAR-γ agonist prevented the development of several of the pathophysiological characteristics associated with the RUPP model of preeclampsia, via a heme oxygenase 1–dependent pathway. The findings from this study provide further insight into the underlying etiology of preeclampsia and a potential therapeutic target for the treatment of preeclampsia.

Background and purpose: Cannabidiol (CBD) is a phytocannabinoid, with anti‐apoptotic, anti‐inflammatory and antioxidant effects and has recently been shown to exert a tissue sparing effect during chronic myocardial ischaemia and reperfusion (I/R). However, it is not known whether CBD is cardioprotective in the acute phase of I/R injury and the present studies tested this hypothesis.Experimental approach: Male Sprague‐Dawley rats received either vehicle or CBD (10 or 50 µg·kg⁻¹i.v.) 10 min before 30 min coronary artery occlusion or CBD (50 µg·kg⁻¹i.v.) 10 min before reperfusion (2 h). The appearance of ventricular arrhythmias during the ischaemic and immediate post‐reperfusion periods were recorded and the hearts excised for infarct size determination and assessment of mast cell degranulation. Arterial blood was withdrawn at the end of the reperfusion period to assess platelet aggregation in response to collagen.Key results: CBD reduced both the total number of ischaemia‐induced arrhythmias and infarct size when administered prior to ischaemia, an effect that was dose‐dependent. Infarct size was also reduced when CBD was given prior to reperfusion. CBD (50 µg·kg⁻¹i.v.) given prior to ischaemia, but not at reperfusion, attenuated collagen‐induced platelet aggregation compared with control, but had no effect on ischaemia‐induced mast cell degranulation.Conclusions and implications: This study demonstrates that CBD is cardioprotective in the acute phase of I/R by both reducing ventricular arrhythmias and attenuating infarct size. The anti‐arrhythmic effect, but not the tissue sparing effect, may be mediated through an inhibitory effect on platelet activation.

Emerging evidence indicates that G‐protein coupled receptor 55 (GPR55), a nonclassic receptor of the endocannabinoid system that is activated by L‐α‐lysophosphatidylinositol and various cannabinoid ligands, may regulate endocrine function and energy metabolism. We examined how GPR55 deficiency and modulation affects insulin signaling in skeletal muscle, adipose tissue, and liver alongside expression analysis of proteins implicated in insulin action and energy metabolism. We show that GPR55‐null mice display decreased insulin sensitivity in these tissues, as evidenced by reduced phosphorylation of PKB/Akt and its downstream targets, concomitant with increased adiposity and reduced physical activity relative to wild‐type counterparts. Impaired tissue insulin sensitivity coincided with reduced insulin receptor substrate‐1 abundance in skeletal muscle, whereas in liver and epididymal fat it was associated with increased expression of the 3‐phosphoinoistide lipid phosphatase, phosphatase and tensin homolog. In contrast, GPR55 activation enhanced insulin signaling in cultured skeletal muscle cells, adipocytes, and hepatocytes; this response was negated by receptor antagonists and GPR55 gene silencing in L6 myotubes. Sustained GPR55 antagonism in 3T3‐L1 adipocytes enhanced expression of proteins implicated in lipogenesis and promoted triglyceride accumulation. Our findings identify GPR55 as a positive regulator of insulin action and adipogenesis and as a potential therapeutic target for countering obesity‐induced metabolic dysfunction and insulin resistance.—Lipina, C., Walsh, S. K., Mitchell, S. E., Speakman, J. R., Wainwright, C. L., Hundal, H. S. GPR55 deficiency is associated with increased adiposity and impaired insulin signaling in peripheral metabolic tissues. FASEB J. 33, 1299–1312 (2019). www.fasebj.org