Metabolic Theory of Preeclampsia: Implications for Maternal Cardiovascular Health.

Preeclampsia (PE) is a multisystemic disorder of pregnancy that not only causes perinatal mortality and morbidity but also has a long-term toll on the maternal and fetal cardiovascular system. Women diagnosed with PE are at greater risk for the subsequent development of hypertension, ischemic heart disease, cardiomyopathy, cerebral edema, seizures, and end-stage renal disease. Although PE is considered heterogeneous, inefficient extravillous trophoblast migration leading to deficient spiral artery remodeling and increased uteroplacental vascular resistance is the likely initiation of the disease. The principal pathophysiology is placental hypoxia, causing subsequent oxidative stress, leading to mitochondrial dysfunction, mitophagy, and immunological imbalance. The damage imposed on the placenta in turn results in the 'stress response' categorized by the dysfunctional release of vasoactive components including oxidative stressors, pro-inflammatory factors, and cytokines into the maternal circulation. These bioactive factors have deleterious effects on systemic endothelial cells and coagulation leading to generalized vascular dysfunction and hypercoagulability. A better understanding of these metabolic factors may lead to novel therapeutic approaches to prevent and treat this multisystemic disorder. In this review, we connect the hypoxic-oxidative stress and inflammation involved in the pathophysiology of PE to the resulting persistent cardiovascular complications in preeclamptic patients.

Emerging therapeutic strategies in hypoxic-ischemic encephalopathy: a focus on cognitive outcomes.

Perinatal hypoxia-ischemia represents a significant risk to CNS development, leading to high mortality rates, diverse damages, and persistent neurological deficits. Despite advances in neonatal medicine in recent decades, the incidence of HIE remains substantial. Motor deficits can manifest early, while cognitive impairments may be diagnosed later, emphasizing the need for extended follow-up. This review aims to explore potential candidates for therapeutic interventions for hypoxic-ischemic encephalopathy (HIE), with a focus on cognitive deficits. We searched randomized clinical trials (RCT) that tested drug treatments for HIE and evaluated cognitive outcomes. The results included studies on erythropoietin, melatonin, magnesium sulfate, topiramate, and a combination of vitamin C and ibuprofen. Although there are several indications of the efficacy of these drugs among animal models, considering neuroprotective properties, the RCTs failed to provide complete effectiveness in the context of cognitive impairments derived from HIE. More robust RCTs are still needed to advance our knowledge and to establish standardized treatments for HIE.

Evaluation of Pain Prevalence in Children Who Experienced Perinatal Hypoxia-Ischemia Events: Characteristics and Associations With Sociodemographic Factors.

INTRODUCTION: Pain in children who suffer from hypoxia-ischemia (HI) events is still not widely studied. Hypoxia-ischemia is characterized by the momentary or permanent cessation of blood flow and, consequently, of oxygen supply, becoming the main cause of encephalopathy in children. Hyperalgesia was identified in animals undergoing prenatal hypoxia-ischemia by researchers from the Universidade do Estado do Rio de Janeiro (UERJ). Premature and asphyxiated newborns have been admitted to the neonatal intensive care unit (NICU) of Pedro Ernesto University Hospital (HUPE) in Brazil and are monitored by the Outpatient Follow-up of High-Risk Newborns Project (SARAR), but no pain assessment was performed. OBJECTIVE: To assess pain in children born in high-risk situations, such as prematurity and perinatal asphyxia, with higher chances of perinatal HI, discharged from the NICU/HUPE, and followed by SARAR. METHODOLOGY: The study was approved by the HUPE Research Ethics Committee. The epidemiological, descriptive, cross-sectional study started in 2021 and finished in 2023, with the application of the pain assessment tool or instrument adapted from the Lübeck Pain-Screening Questionnaire to the caregivers and with the collection of growth and development data. The population consisted of asphyxiated infants born with a gestational age greater than 35 weeks and submitted to the Therapeutic Hypothermia protocol and premature infants discharged from the NICU between two (gestational age 1 (GA1)) and 12 years old. For most of them, pain prevalence was assessed according to its frequency and intensity, as were sociodemographic variables of the child and mother, neural alterations, and the Children's Developmental Scale (DENVER II). The percentage differences between the evaluated factors and the presence of pain were performed using Fisher's exact test and medians using the non-parametric Wilcoxon rank-sum test, both appropriate for the small sample of children. Significance levels of 10% were considered for trends and 5% for statistically significant differences. RESULTS: Of the 86 children included in our search, 26 (30%) were born with a gestational age greater than 35 weeks and diagnosed with perinatal asphyxia (hereinafter referred to as the asphyxiation group), and 60 (70%) were premature. Pain was reported by 22 (25%) children, of whom 54.4% reported moderate or severe pain. The head and abdomen were the most reported sites (36%). Differences were observed in the percentage distribution of pain between asphyxiates and premature infants (11% vs. 32%; p-value 0.061 on the Fisher test) and between females and males (34% vs. 17%; p-value 0.085 on the Fisher test). Black and Brown children had higher median pain scale values than White children (p-value < 0.027, Wilcoxon rank sum test). CONCLUSION: There is a higher prevalence of pain in girls, in the head, in premature infants, and greater intensity among Black and Brown children. Therefore, knowing the pain profile can help improve their quality of life by offering treatments.

Human Mesenchymal Stem Cell Therapy Reverses Su5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Mice.

Aims: Pulmonary arterial hypertension (PAH) is a disease characterized by an increase in pulmonary vascular resistance and right ventricular (RV) failure. We aimed to determine the effects of human mesenchymal stem cell (hMSC) therapy in a SU5416/hypoxia (SuH) mice model of PAH. Methods and Results: C57BL/6 mice (20-25 g) were exposure to 4 weeks of hypoxia combined vascular endothelial growth factor receptor antagonism (20 mg/kg SU5416; weekly s.c. injections; PAH mice). Control mice were housed in room air. Following 2 weeks of SuH exposure, we injected 5 × 105 hMSCs cells suspended in 50 µL of vehicle (0.6 U/mL DNaseI in PBS) through intravenous injection in the caudal vein. PAH mice were treated only with vehicle. Ratio between pulmonary artery acceleration time and RV ejection time (PAAT/RVET), measure by echocardiography, was significantly reduced in the PAH mice, compared with controls, and therapy with hMSCs normalized this. Significant muscularization of the PA was observed in the PAH mice and hMSC reduced the number of fully muscularized vessels. RV free wall thickness was higher in PAH animals than in the controls, and a single injection of hMSCs reversed RV hypertrophy. Levels of markers of exacerbated apoptosis, tissue inflammation and damage, cell proliferation and oxidative stress were significantly greater in both lungs and RV tissues from PAH group, compared to controls. hMSC injection in PAH animals normalized the expression of these molecules which are involved with PAH and RV dysfunction development and the state of chronicity. Conclusion: These results indicate that hMSCs therapy represents a novel strategy for the treatment of PAH in the future.

Novel agonist of α4ß2* neuronal nicotinic receptor with antinociceptive efficacy in rodent models of acute and chronic pain.

OBJECTIVE: To demonstrate the antinociceptive and antihypersensitivity mechanisms of Cris-104 (1-{2-[5-(4-fluorophenyl)-1H-pyrazol-4-yl]ethyl}piperidine), a novel selective α4ß2* nicotinic acetylcholine receptor (nAChR) agonist, in rodent acute/inflammatory and chronic pain models. MATERIALS AND METHODS: Hot-plate and formalin tests in mice were used to examine Cris-104-induced antinociceptive effects on thermal/inflammatory pain. Cris-104 effects on hypersensitivity, norepinephrine (NE) release in the spinal dorsal horn, and neuronal activity in the locus coeruleus (LC) were examined in rats with lumbar spinal nerve ligation using behavioral, microdialysis, and extracellular recording methods. Cris-104 effects on spontaneous locomotion were examined in an open-field test. RESULTS: Cris-104 induced dose-dependent antinociception effects in hot-plate and formalin tests, and these effects were blocked by the general nAChR antagonist mecamylamine, the selective α4ß2* nAChR antagonist dihydro-beta-erythroidine, and the α2-adrenoceptor antagonist yohimbine, but not by the α1-adrenoceptor antagonist prazosin. Systemic and spinally perfused Cris-104 increased NE concentrations in microdialysates from the spinal cord in both normal and SNL rats. Systemic Cris-104 increased neuronal activity in the LC of normal rats. Mecamylamine blocked the effects of Cris-104 on spinal NE release and LC neuronal activity. Systemic Cris-104 did not affect locomotor activity significantly. CONCLUSION: The α4ß2 neuronal nAChR agonist, Cris-104, was effective for treatment of pain via descending noradrenergic inhibition of pain signaling.

Cardioprotection Induced by Activation of GPER in Ovariectomized Rats With Pulmonary Hypertension.

Pulmonary hypertension (PH) is a disease of women (female-to-male ratio 4:1), and is associated with cardiac and skeletal muscle dysfunction. Herein, the activation of a new estrogen receptor (GPER) by the agonist G1 was evaluated in oophorectomized rats with monocrotaline (MCT)-induced PH. Depletion of estrogen was induced by bilateral oophorectomy (OVX) in Wistar rats. Experimental groups included SHAM or OVX rats that received a single intraperitoneal injection of MCT (60 mg/kg) for PH induction. Animals received s.c. injection of either vehicle or G1, a GPER agonist, (400 µg/kg/day) for 14 days after the onset of disease. Rats with PH exhibited exercise intolerance and cardiopulmonary alterations, including reduced pulmonary artery flow, biventricular remodeling, and left ventricular systolic and diastolic dysfunction. The magnitude of these PH-induced changes was significantly greater in OVX versus SHAM rats. G1 treatment reversed both cardiac and skeletal muscle functional aberrations caused by PH in OVX rats. G1 reversed PH-related cardiopulmonary dysfunction and exercise intolerance in female rats, a finding that may have important implications for the ongoing clinical evaluation of new drugs for the treatment of the disease in females after the loss of endogenous estrogens.

Adenosine Receptors As Drug Targets for Treatment of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a clinical condition characterized by pulmonary arterial remodeling and vasoconstriction, which promote chronic vessel obstruction and elevation of pulmonary vascular resistance. Long-term right ventricular (RV) overload leads to RV dysfunction and failure, which are the main determinants of life expectancy in PAH subjects. Therapeutic options for PAH remain limited, despite the introduction of prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and soluble guanylyl cyclase stimulators within the last 15 years. Through addressing the pulmonary endothelial and smooth muscle cell dysfunctions associated with PAH, these interventions delay disease progression but do not offer a cure. Emerging approaches to improve treatment efficacy have focused on beneficial actions to both the pulmonary vasculature and myocardium, and several new targets have been investigated and validated in experimental PAH models. Herein, we review the effects of adenosine and adenosine receptors (A1, A2A, A2B, and A3) on the cardiovascular system, focusing on the A2A receptor as a pharmacological target. This receptor induces pulmonary vascular and heart protection in experimental models, specifically models of PAH. Targeting the A2A receptor could potentially serve as a novel and efficient approach for treating PAH and concomitant RV failure. A2A receptor activation induces pulmonary endothelial nitric oxide synthesis, smooth muscle cell hyperpolarization, and vasodilation, with important antiproliferative activities through the inhibition of collagen deposition and vessel wall remodeling in the pulmonary arterioles. The pleiotropic potential of A2A receptor activation is highlighted by its additional expression in the heart tissue, where it participates in the regulation of intracellular calcium handling and maintenance of heart chamber structure and function. In this way, the activation of A2A receptor could prevent the production of a hypertrophic and dysfunctional phenotype in animal models of cardiovascular diseases.

Activation of GPER ameliorates experimental pulmonary hypertension in male rats.

RATIONALE: Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling that leads to pulmonary congestion, uncompensated right-ventricle (RV) failure, and premature death. Preclinical studies have demonstrated that the G protein-coupled estrogen receptor (GPER) is cardioprotective in male rats and that its activation elicits vascular relaxation in rats of either sex. OBJECTIVES: To study the effects of GPER on the cardiopulmonary system by the administration of its selective agonist G1 in male rats with monocrotaline (MCT)-induced PH. METHODS: Rats received a single intraperitoneal injection of MCT (60mg/kg) for PH induction. Experimental groups were as follows: control, MCT+vehicle, and MCT+G1 (400µg/kg/daysubcutaneous). Animals (n=5pergroup) were treated with vehicle or G1 for 14days after disease onset. MEASUREMENTS AND MAIN RESULTS: Activation of GPER attenuated exercise intolerance and reduced RV overload in PH rats. Rats with PH exhibited echocardiographic alterations, such as reduced pulmonary flow, RV hypertrophy, and left-ventricle dysfunction, by the end of protocol. G1 treatment reversed these PH-related abnormalities of cardiopulmonary function and structure, in part by promoting pulmonary endothelial nitric oxide synthesis, Ca2+ handling regulation and reduction of inflammation in cardiomyocytes, and a decrease of collagen deposition by acting in pulmonary and cardiac fibroblasts. CONCLUSIONS: G1 was effective to reverse PH-induced RV dysfunction and exercise intolerance in male rats, a finding that have important implications for ongoing clinical evaluation of new cardioprotective and vasodilator drugs for the treatment of the disease.