Pial Vessel-Associated Microglia/Macrophages Increase in Female Dahl-SS/Jr Rats Independent of Pregnancy History.

As the resident immune cells of the central nervous system, microglia have a wide range of functions such as surveillance, phagocytosis, and signaling through production of chemokines and cytokines. Recent studies have identified and characterized macrophages residing at the meninges, a series of layers surrounding the brain and spinal cord. While perivascular microglia within the brain parenchyma increase following chronic hypertension, there are no reports of changes at the meninges, and specifically, associated with the pial vasculature. Thus, we used female Sprague Dawley and Dahl salt-sensitive (SS/Jr) rat brains, stained for ionized calcium-binding adapter molecule (Iba1), and characterized microglia/macrophages associated with pial vessels in the posterior brain. Results indicate that Iba1+ pial vessel-associated microglia (PVAM) completely surrounded the vessels in brains from the Dahl-SS/Jr rats. PVAM density was significantly higher and distance between PVAMs lower in Dahl-SS/Jr compared to the Sprague Dawley rat brains. Pregnancy history did not affect these findings. While the functional role of these cells are not known, we contextualize our novel findings with that of other studies assessing or characterizing myeloid cells at the borders of the CNS (meninges and choroid plexus) and perivascular macrophages and propose their possible origin in the Dahl-SS/Jr model of chronic hypertension.

Endothelial cell disruption drives increased blood-brain barrier permeability and cerebral edema in the Dahl SS/jr rat model of superimposed preeclampsia.

Preeclampsia is characterized by increases in blood pressure and proteinuria in late pregnancy, and neurological symptoms can appear in the form of headaches, blurred vision, cerebral edema, and, in the most severe cases, seizures (eclampsia). The causes for these cerebral manifestations remain unknown, so the use of animal models that mimic preeclampsia is essential to understanding its pathogenesis. The Dahl salt-sensitive (Dahl SS/jr) rat model develops spontaneous preeclampsia superimposed on chronic hypertension; therefore, we hypothesized that the Dahl SS/jr rat would display cerebrovascular features similar to those seen in human preeclampsia. Furthermore, we predicted that this model would allow for the identification of mechanisms underlying these changes. The pregnant Dahl SS/jr rat displayed increased cerebral edema and blood-brain barrier disruption despite tighter control of cerebral blood flow autoregulation and vascular smooth muscle myogenic tone. Analysis of cerebral endothelial cell morphology revealed increased opening of tight junctions, basement membrane dissolution, and vesicle formation. RNAseq analysis identified that genes related to endothelial cell tight junctions and blood-brain barrier integrity were differentially expressed in cerebral vessels from pregnant Dahl SS/jr compared with healthy pregnant Sprague Dawley rats. Overall, our data reveal new insights into mechanisms involved in the cerebrovascular dysfunction of preeclampsia.NEW & NOTEWORTHY This study uses the Dahl SS/jr rat as a preclinical model of spontaneous superimposed preeclampsia to demonstrate uncoupling of cerebral vascular permeability and blood-brain barrier disruption from cerebral blood flow autoregulatory dysfunction and myogenic tone. Additionally, the data presented in this study lay the foundational framework on which future experiments assessing specific transcellular transport components such as individual transporter protein expression and components of the vesicular transport system (caveolae) can be built to help reveal a potential direct mechanistic insight into the causes of cerebrovascular complications during preeclamptic pregnancies.

The glucagon-like peptide 1 receptor agonist liraglutide attenuates placental ischemia-induced hypertension.

Preeclampsia is a hypertensive disorder of pregnancy characterized by systemic perturbations of nitric oxide function, reflective of generalized endothelial dysfunction. Therapies that target the nitric oxide pathway have shown promise in both clinical and preclinical studies of preeclampsia. The glucagon-like peptide 1 agonists have been shown to increase nitric oxide and lower blood pressure in patients with diabetes, in part, through activation of nitric oxide synthase (NOS). Therefore, we hypothesized that a direct acting glucagon-like peptide 1 receptor agonist would improve stigmata of the preeclampsia syndrome. Using the reduced uterine perfusion pressure rat model, we found that treatment with liraglutide significantly lowered blood pressure, improved renal function, and upregulated NOS3 protein expression in the mesenteric arterial bed. However, there were adverse effects on pup growth that were likely related to diminished food intake in the dams. Collectively, these data support the premise that the use of drugs that improve NOS abundance, including the glucagon-like peptide 1 agonists, is a rational therapeutic approach to the treatment of preeclampsia, but suggest cautious and careful study of their safety before potential clinical use in humans.NEW & NOTEWORTHY Drugs that target the glucagon-like peptide-1 pathway such as liraglutide are already used clinically, and it has been shown to promote endothelial nitric oxide synthase (NOS3) expression. We demonstrate that liraglutide, a glucagon-like peptide 1 receptor (GLP-1R) agonist, lowers blood pressure, improves renal function, and upregulates NOS3 in a rat model of placental ischemia. These data suggest that drugs that target the nitric oxide system, including GLP-1R agonists, are a potential therapeutic option for preeclampsia.

Spontaneous superimposed preeclampsia: chronology and expression unveiled by temporal transcriptomic analysis.

Preeclampsia (PE), a multifactorial pregnancy-specific syndrome accounting for up to 8% of pregnancy complications, is a leading cause of maternal and fetal morbidity and mortality. PE is also associated with long-term risk of hypertension and stroke for both mother and fetus. Currently, the only "cure" is delivery of the baby and placenta, largely because the pathogenesis of PE is not yet fully understood. PE is associated with impaired vascular remodeling at the maternal-fetal interface and placental insufficiency; however, specific factors contributing to this impairment have not been identified. To identify molecular pathways involved in PE, we examined temporal transcriptomic changes occurring within the uterus, uterine implantation sites, and placentae from the Dahl salt-sensitive (Dahl S) rat model of superimposed PE compared with Sprague Dawley (SD) rats. We hypothesized that targeted gene analysis and whole transcriptome analysis would identify genetic factors that contribute to development of the preeclamptic phenotype in the Dahl S rat and unveil novel biomarkers, therapeutic targets, and mechanistic pathways in PE. Quantitative real-time PCR (qRT-PCR) and whole genome microarray analysis were performed on isolated total RNA from uterus (day 0), uterine implantation sites (days 7 and 10), and placenta (days 14 and 20). We found 624, 332, 185, and 366 genes to be differentially expressed between Dahl S (PE) and SD (normal pregnancy) on days 0, 7, 10, and 14, respectively. Our data revealed numerous pathways that may play a role in the pathophysiology of spontaneous superimposed PE and allow for further investigation of novel therapeutic targets and biomarker development.

Expansion of regulatory T cells using low-dose interleukin-2 attenuates hypertension in an experimental model of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disorder that is characterized by prevalent hypertension, renal injury, and cardiovascular disease. Numerous studies have reported a low prevalence and/or impaired function of regulatory T (TREG) cells in both patients with SLE and murine models of the disease. Evidence suggests that TREG cell dysfunction in SLE results from a deficiency in IL-2. Recent studies have reported that low-dose IL-2 therapy expands TREG cells in mouse models of SLE, but whether expanding TREG cells protects against hypertension and renal injury during SLE is unclear. To examine this question, female SLE (NZBWF1) and control (NZW) mice were injected with vehicle or recombinant mouse IL-2 three times in 24 h followed by single maintenance doses every 5 days for 4 wk. Treatment with IL-2 effectively expanded TREG cell populations in the peripheral blood, spleen, and kidneys. Circulating levels of anti-dsDNA IgG autoantibodies, a marker of SLE disease activity, were higher in SLE mice compared with control mice but were unaffected by IL-2 treatment. As previously reported by our laboratory, mean arterial pressure, measured in conscious mice by a carotid catheter, was higher in SLE mice than in control mice. Mean arterial pressure was significantly lower in IL-2-treated SLE mice compared with vehicle-treated SLE mice, suggesting that expanding TREG cells using low-dose IL-2 attenuates the development of hypertension. While the mechanism for the protection against hypertension is unclear, it does not appear to be related to the delay of SLE disease progression.