Excessive hypercholesterolemia (eHC) in pregnancy is associated with complications such as preeclampsia, yet its impact on maternal cardiac adaptation and long-term cardiovascular health remains unclear. We hypothesized that eHC impairs maternal cardiac structure and function during pregnancy and that these effects persist postpartum. Sprague Dawley rats were fed either a control diet (CTL) or high cholesterol diet (eHC) from gestational day (GD) 6-20 (term=22 days). Echocardiography was performed before pregnancy, at GD20, and 3 months postpartum. Plasma and left ventricular tissue were collected at GD20 and postpartum for molecular analyses. CTL dams demonstrated normal pregnancy-associated cardiac adaptations, including increased diastolic left ventricular internal diameter, stroke volume, cardiac output, and diastolic left ventricular volume in late pregnancy, with normalization postpartum. These adaptations were attenuated in eHC dams. In late pregnancy, eHC dams exhibited reduced stroke volume and cardiac output compared with CTL, along with alterations in diastolic function, including reduced mitral valve A' velocity. Postpartum, eHC dams showed changes in diastolic indices, including reduced mitral valve A-wave velocity and E'/A' ratio. Measures of systolic performance (ejection fraction and fractional shortening) were unchanged between groups. Molecular analyses revealed increased cardiomyocyte size, altered collagen remodeling characterized by an increased COL1-to-COL3 ratio, and elevated CD31 expression in eHC dams during pregnancy. Postpartum, collagen remodeling was evident, but now with reduced COL1 and increased COL3 expression. Together, these findings demonstrate that eHC disrupts normal maternal cardiac adaptation during pregnancy and promotes adverse remodeling and cardiac dysfunction postpartum, with potential implications for long-term cardiovascular disease risk.
Preclinical porcine models of myocardial infarction (MI) are essential for cardiovascular research but often require lengthy surgeries with variable outcomes. We developed a minimally invasive mini-thoracotomy approach to maximize procedural success, minimize operative time, and ensure reproducible infarct induction. Eleven Lanyu Miniature Pigs (25-30 kg) were assigned to an MI group (n = 7) or sham control group (n = 4). MI was induced by permanent left anterior descending (LAD) coronary artery ligation via mini-thoracotomy. Six of seven MI pigs (85.7%) survived, with a mean skin-to-skin operative time of 35.83 ± 2.86 minutes, whereas all sham controls survived without complications. Infarction was confirmed by post-ligation ST-segment elevation and pathological Q waves. Serial echocardiography and speckle-tracking strain analysis at baseline, 1 week, and 3 months revealed consistent regional systolic dysfunction in the MI group, though inter-animal variability was observed in certain functional parameters. Cross-sectional area-based ejection fraction was significantly reduced at the papillary muscle and apical levels by 1 week, persisting through 3 months. Speckle-tracking showed corresponding reductions in radial strain, particularly apically. Progressive ventricular remodeling was evident from an increased left ventricular mass index, and Masson's trichrome staining confirmed extensive myocardial fibrosis distal to the ligation sites (mean fibrotic area 25.6 ± 4.3%). Sham controls retained preserved structure and function throughout. In conclusion, this minimally invasive porcine MI model provides a highly feasible, rapid, and reproducible translational platform, integrating surgical accessibility with robust functional and histological validation for investigating post-infarction remodeling and evaluating cardiovascular therapeutics.
Higher diastolic aortic pressure is associated with central arterial elastic recoil function and may help preserve peripheral perfusion. Japanese female pearl divers, called "Ama," exhibit lower arterial stiffness as an adaptation to lifelong repeated diving, but whether this translates into enhanced diastolic blood flow remains unclear. This study investigated aortic and carotid hemodynamic profiles to determine whether female pearl divers demonstrate enhanced diastolic blood flow in association with diastolic aortic pressure. A total of 61 middle-aged and elderly female pearl divers (<65-yr group: n = 23, 53 ± 9 yr; ≥65-yr group: n = 38, 72 ± 4 yr, representing middle-aged and older groups, respectively) and 94 female nondivers (<65-yr group: n = 48, 53 ± 9 yr; ≥65-yr group: n = 46, 73 ± 5 yr) were studied. Aortic pressure was estimated from applanation tonometry of carotid arterial pressure waveforms via a general transfer function. Carotid blood flow was calculated from blood velocity and diameter of the common carotid artery. Diastolic aortic pressure-time integral and carotid flow volume were calculated as areas under the waveforms from the dicrotic notch to end-diastole. Compared with nondivers, pearl divers exhibited a higher diastolic aortic pressure-time integral (main effect of group, P < 0.01). Moreover, diastolic carotid blood flow volume was also greater in pearl divers than in nondivers (main effect of group, P < 0.01). Therefore, compared with female nondivers, lifelong female pearl divers may have lower central arterial stiffness that enhances diastolic aortic pressure, thereby preserving greater carotid blood flow during diastole.NEW & NOTEWORTHY This study indicated that, compared with female nondivers, lifelong female pearl divers exhibited higher diastolic carotid blood flow alongside higher aortic pressure during diastole. Therefore, lifelong repeated diving exposure may lead to decreased arterial stiffness, which can facilitate higher diastolic aortic pressure and thereby enhance distal arterial blood flow during diastole.
Smoking disrupts cardiac autonomic regulation, vascular biology, and platelet function; however, the acute and longer-term cardiovascular effects of resurging and emerging tobacco and marijuana products remain incompletely characterized. We investigated the impact of exposure to smoke and aerosol from several tobacco and marijuana products on cardiac function, platelet activity, and myocardial susceptibility to ischemia/reperfusion myocardial infarction (MI). Male/female Sprague-Dawley rats underwent single or daily 5-min pulsatile exposure sessions to emissions from tobacco cigarettes, e-cigarettes (JUUL), heated tobacco products (IQOS), marijuana cigarettes, or cannabinoid-depleted ("placebo") marijuana cigarettes; with an air negative control. Cardiac function was assessed immediately after single exposure using echocardiography and intraventricular hemodynamics. Platelet aggregation was measured immediately after single exposure and one day after repeated (2-week) exposure. Myocardial infarct size, normalized to area-at-risk, was assessed following MI after repeated (4-week) exposure. Single exposure to tobacco smoke or JUUL aerosol reduced left ventricular ejection fraction relative to pre-exposure. Acute marijuana smoke exposure similarly impaired left ventricular function assessed by hemodynamics. Single exposure to tobacco, marijuana, and placebo marijuana smoke increased collagen-induced platelet aggregation, with more pronounced responses in females, whereas repeated (2-week) exposure to smoke/aerosol from tobacco cigarettes, JUUL, IQOS, and placebo marijuana increased platelet aggregation across groups. Notably, repeated (4-week) exposure to tobacco smoke/aerosol or marijuana smoke prior to MI reduced myocardial tissue preservation, resulting in greater infarct size post-MI. These findings indicate that individual tobacco and marijuana smoking and vaping similarly impair cardiac function, enhance platelet reactivity, and reduce myocardial tolerance to ischemia/reperfusion injury.
The salt sensitivity of blood pressure (SSBP) is rarely assessed and represents a critical barrier in precision hypertension treatment. The current approaches to assess salt sensitivity are labor and resource intensive limiting their clinical implementation. The salt sensitivity index (SSI), derived from 24-hour ambulatory blood pressure monitoring (ABPM) data, has been proposed as a clinical diagnostic approach to classify individuals at low-, intermediate-, or high-risk for the SSBP. This study utilized the Dietary Approaches to Stop Hypertension (DASH)-Sodium Trial control diet arm dataset (N=170), in which the SSBP was assessed by the gold standard dietary approach, to address the hypothesis that identification of a high-risk SSI can predict the individual SSBP. In the high-risk SSI category 72% of DASH-Sodium Trial participants exhibited a salt-sensitive phenotype. For all participants with a high-risk SSI (male and female and normotensive and hypertensive) sensitivity (ability to correctly identify individuals with the SSBP) was 85%, specificity (ability to correctly identify individuals without the SSBP) was 41%, positive predictive value (probability that a person who tests positive has the SSBP) was 72%, negative predictive value was 60% (probability that a person who tests negative does not have the SSBP) and accuracy was 69%. For hypertensive participants only with a high-risk SSI (males and females), sensitivity was 86%, specificity was 44%, the positive predictive value increased to 83%, the negative predictive value was 50% and accuracy increased to 76%. This study validates the identification of a high-risk SSI, based on 24-hour ABPM, as a generalizable implementable approach for the clinical diagnosis of the SSBP, with a potential greater clinical diagnostic value in hypertensive versus normotensive individuals.
Acute kidney injury (AKI) affects up to 50% of patients undergoing cardiopulmonary bypass, yet early diagnostic biomarkers and targeted therapies remain limited. Although AKI is attributed to bypass-induced renal ischemia, the underlying molecular mechanisms are poorly understood. This study characterizes renal inflammatory dynamics in cardiac surgery patients, beginning intraoperatively. One hundred adults undergoing cardiopulmonary bypass were enrolled at the Quebec Heart and Lung Institute in Canada (July 2021 - April 2024). Urine and plasma samples were collected before and up to 5 days post-bypass. Pro-inflammatory P2Y14 receptor ligands (UDP-sugars) were quantified by LC-ESI-MS/MS, and kidney injury marker-1 (KIM-1) and inflammatory mediators were measured by multiplex immunoassays. AKI was defined using modified KDIGO criteria: serum creatinine increase ≥ 0.3 mg/dL or urine output ≤ 0.5 mL/kg/h for 24 hours postoperatively. Urinary UDP-sugars increased significantly within 0-4 hours post-bypass in AKI patients, while plasma levels remained unchanged. Urinary UDP-sugars correlated with KIM-1 at 4 hours and preceded pro-inflammatory cytokines (CXCL1, CCL2, and IL-18), which peaked at 12 hours. Immunofluorescence localized P2Y14 to collecting duct apical membranes, and detected CD45+/myeloperoxidase (MPO)+ neutrophils in ischemic human kidneys. Patients with elevated UDP-sugars showed significantly higher inflammatory markers compared to those with low levels. In conclusion, UDP-sugars released by damaged renal tubules trigger inflammatory cytokine secretion in AKI patients. The UDP-sugar/P2Y14 axis represents a novel early predictor and therapeutic target for cardiac surgery-associated AKI. The robust expression of P2Y14 and the presence of proinflammatory immune cells in human ischemic kidneys further support the potential of this therapeutic strategy.
Understanding the causes of ventricular arrhythmias after myocardial infarction (MI) remains a major challenge to academic and clinical medicine. Key concepts in the pathophysiology underlying such events are based on studies in rodents, in whom altered sarcoplasmic reticulum (SR) calcium handling is key even in chronic stages after MI. Since cardiac electrophysiology in rodents has important differences from humans, an overview of insights directly from large animals and humans is needed. Our objective was to provide a summary of existing literature on the role of SR calcium handling in ventricular tachyarrhythmias after the acute phase of MI in large animals and humans. We conducted a systematic search of original articles on calcium handling after MI in large animals and humans, summarized key findings, and assessed risk of bias in the included articles. Twenty-five studies explicitly measuring cellular calcium handling after MI in large animals or human tissue were included. Overall, the studies were somewhat ambiguous regarding calcium transient amplitude and kinetics; but consistently showed increased frequency of calcium sparks, calcium waves, delayed afterdepolarizations and reduced t-tubule density; and some reported increased propensity for calcium alternans. Abundance and posttranslational modification of calcium handling proteins were less consistent. In conclusion, existing evidence from large animals and human material supports a role for altered calcium handling in ventricular arrhythmias after MI. However, the evidence is still limited. More studies in such models are needed to provide mechanistic explanations that can be used as a basis for development of new therapies.
Cardiac arrhythmias are suspected as a major cause of sudden cardiac death (SCD) in pulmonary arterial hypertension (PAH); however, the mechanisms underlying right ventricle (RV) electrical remodeling, arrhythmias, and SCD in PAH remain unclear. We investigated the mechanisms of increased susceptibility to SCD during progressive PAH in the Fischer CDF rat monocrotaline (MCT) model. Echocardiography, electrocardiogram, and cardiac catheterization were performed at 4 and 5 wk post MCT injection (MCT-4 and MCT-5 groups, respectively). Hearts were isolated and Langendorff-perfused, and changes in action potential (AP) duration (APD) were evaluated by voltage optical mapping. A progressive increase in RV systolic pressure was observed in MCT-4 and MCT-5 compared to control. In MCT-4, we observed RV hypertrophy with preserved cardiac function and chamber size, indicating adaptive RV remodeling. Conversely, maladaptive RV remodeling was seen in MCT-5, indicated by reduced cardiac function, along with increased RV internal diameter. Electrically, we observed delayed repolarization and prolongation of RV AP and QT interval in the MCT-5 compared to control and MCT-4. Electrical changes were consistent with decreased Kcnh2, Kcnk2, and Scn7a expression in the RV. Reduced RV vascular density together with upregulation of hypoxia-regulated genes were noted in MCT-5 compared to control, which along with the observed ST elevation suggests RV ischemia. In summary, Fischer CDF rats develop maladaptive RV functional and electrical remodeling at 5 wk post MCT that is associated with reduced RV potassium and sodium channel expression and elevated markers of RV ischemia. These changes may contribute to increased susceptibility to arrhythmias and SCD in PAH.NEW & NOTEWORTHY This study shows maladaptive right ventricle (RV) functional and electrical remodeling in pulmonary arterial hypertension (PAH) in Fischer CDF rats, a rat strain that is susceptible to sudden cardiac death in PAH. The electrical changes in the RV were associated with reduced expression of potassium and sodium channels in the RV, reduced RV vascular density, and elevated markers of RV ischemia. Combination of these changes may increase the risk of sudden cardiac death in PAH.
Patients with chronic inflammatory disorders, including inflammatory bowel disease (IBD), carry an increased risk of cardiovascular disease. The 2022 ORAL Surveillance study reported that the pan-selective Janus kinase inhibitor (JAKi) tofacitinib was associated with increased risk of major adverse cardiovascular events (MACE) among patients with rheumatoid arthritis compared with antitumor necrosis factor (anti-TNF) therapy. This prompted guideline changes regarding the use of all JAKis, including upadacitinib, a JAK1-selective drug approved for use in chronic inflammatory conditions, including IBD. However, the mechanism underlying JAKi-related MACE outcomes and the significance of JAK selectivity relative to TNF inhibition remain unclear. Microvascular dysfunction (MVD) is a predictor of MACE. Flow-mediated dilation (FMD) is a measure of MVD. Using an established ex vivo model of resistance arterioles isolated from adipose tissue, we performed the first mechanistic comparison of antitumor necrosis factor (anti-TNF; infliximab), pan-JAK inhibitor (tofacitinib), and JAK1-selective (upadacitinib) therapies on human microvascular endothelial function. Arterioles were obtained from low-cardiovascular-risk subjects of both sexes. Isolated microvessels were incubated with drugs of interest. Flow-mediated dilation (FMD), an assessment of MVD, was measured before and after nitric oxide (NO) synthase inhibition or hydrogen peroxide (H2O2) scavenging. No therapy statistically altered FMD magnitude, yet underlying mechanisms differed. Control and infliximab-treated vessels maintained physiologic NO-mediated dilation. Tofacitinib induced a shift toward pathologic H2O2-mediated dilation. Upadacitinib impaired NO-dependent dilation without evidence of compensatory H2O2 signaling. In summary, anti-TNF therapy and selective versus nonselective JAKi differentially modulate endothelial mechanisms of vasodilation, suggesting unique microvascular phenotypes with potential implications for cardiovascular risk.NEW & NOTEWORTHY This is the first ex vivo mechanistic comparison of antitumor necrosis factor therapy (infliximab) and selective (upadacitinib) versus nonselective (tofacitinib) Janus kinase inhibition in human microvessels. Flow-mediated dilation showed no statistical differences; however, the mechanisms driving endothelial dilation varied. We report a shift from nitric oxide- to hydrogen peroxide-mediated dilation with tofacitinib, a distinct phenotype with upadacitinib, and nitric oxide-dependent dilation with infliximab, suggesting differential effects of IBD therapies on microvascular endothelial physiology.
Reported prevalence of cardiovascular disease (CVD) risk factors and phenotypes varies widely. In multi-cohort analyses, such variation reflects population risk, care setting, and data capture. We harmonized baseline data from four analytic cohorts (N=54,188, aged ≥50 years) in five GLOB-cAGE member studies: pooled community (n=956), primary care (n=49,849), acute CVD registry (n=2,723), and chronic CVD cohort (n=660). Any risk-factor was hypertension, diabetes, or dyslipidemia. Any CVD phenotype was ischemic heart disease, heart failure, or atrial fibrillation/flutter. At age 60-74 years, any risk-factor prevalence ranged from 10.4% in primary care to 91.4% in the acute CVD registry (P<0.001); any CVD phenotype prevalence ranged from 4.4% to 47.0% (P<0.001). In the pooled community cohort, any risk-factor prevalence increased from 28.9% at age 50-59 to 85.0% at ≥75 (adjacent q<0.001), while age-sex-standardized any CVD phenotype prevalence remained comparatively low (10.6%). Any CVD phenotype prevalence increased with risk-factor-count, with the clearest gradients in the acute CVD registry (35.8% to 64.2%; P for trend<0.001) and pooled community cohort (6.4% to 19.6%; P for trend<0.001). Among participants with any CVD phenotype, female age distributions were older than male distributions in primary care and the acute CVD registry (female-minus-male median age difference, +3.7 and +5.0 years; both P<0.001). Across diverse care settings, harmonized summary constructs identified interpretable patterns in cardiovascular risk and CVD burden. These real-world data support cardiovascular prevention across ageing, highlight substantial CVD burden among women at older ages, and provide a framework for longitudinal analyses across real-world cohorts.
Iliofemoral vascular tortuosity may reflect vascular aging, yet natural anatomic variation remains poorly characterized at scale. In this single-center retrospective study, we quantified arterial and venous iliofemoral tortuosity in a large cohort of adults with contrast-enhanced abdominopelvic computed tomography (CT) scans. Using an nnU-Net-based deep learning pipeline, iliofemoral arteries and veins were segmented from CT images. Representative centerlines were extracted and mean centerline curvature was computed to quantify tortuosity. Primary analyses explored associations of arterial and venous tortuosity with core covariates: age, biological sex, race, body mass index, height, and smoking status. Secondary analyses evaluated associations with clinical comorbidities and medication exposures. Complete-case analytic cohorts included 725 patients for arterial analyses and 718 for venous analyses. After adjustment for core covariates, age was positively associated with both arterial and venous tortuosity, with a stronger association for arteries than veins (+15% vs +6% per decade). Tortuosity variability among the cohort was higher for arteries than veins (2.2-fold higher residual variance). Female sex was associated with lower arterial and venous tortuosity. Traditional atherosclerotic risk factors, including hypertension, hyperlipidemia, and diabetes, were not associated with iliofemoral tortuosity. After adjustment for co-occurring conditions, end-stage renal disease was associated with lower arterial and venous tortuosity, and congestive heart failure was associated with lower venous tortuosity. Connective tissue disease was associated with higher venous tortuosity. These findings demonstrate distinct arterial, venous, age-related, and sex-related patterns of iliofemoral tortuosity. Additionally, they provide morphometric context for studies evaluating large-vessel geometry and vascular stiffness, hemodynamics, and disease-specific procedural outcomes.
Heart failure with preserved ejection fraction (HFpEF) is a multisystemic syndrome that accounts for more than half of all heart failure cases and causes a substantial burden of morbidity and mortality. In contrast to heart failure with reduced ejection fraction (HFrEF), few disease-modifying therapies exist for HFpEF, reflecting differences in pathophysiology. Low fermentable fiber (FF) intake, gut dysbiosis, and depletion of short-chain fatty acids (SCFAs), microbial metabolites central to immune, metabolic, and vascular homeostasis, are increasingly linked to the pathophysiology of HFpEF. Here, we synthesize preclinical and clinical evidence on FF and SCFAs and evaluate their therapeutic relevance to HFpEF. Preclinical studies demonstrate that FF supplementation or direct SCFA administration improves cardiometabolic function and attenuates cardiac remodeling through SCFA receptor signaling, enhanced nitric oxide bioavailability, reduced inflammation, and metabolic support of the energy-starved failing heart. Supporting the translational relevance of these findings, a systematic review of 27 human randomized controlled trials showed that FF interventions exert microbiome-mediated effects, enriching SCFA-producing taxa and augmenting fecal and circulating SCFA levels, while improving insulin sensitivity and reducing abdominal adiposity and LDL cholesterol. Direct SCFA supplementation increases SCFA availability and provides modest metabolic benefits, including reduced adiposity and liver fat. However, its effects are inconsistent. Collectively, these findings provide a mechanistic and translational rationale for FF-based interventions in HFpEF. To date, no clinical trials have evaluated the effects of FF on HFpEF-specific outcomes. Clinical studies are therefore needed to determine whether increasing FF intake can improve symptoms, cardiac function, and disease progression in HFpEF.
Age- and disease-related declines in brain health contribute to impairments in physical function, yet effective approaches to lessen these declines remain limited. Overall health is governed by a network of interdependent organ systems, such that dysfunction in one system can propagate across others. Although the brain has been viewed as a top-down regulator of vital functions, evidence indicates that cognition is affected by signals from peripheral organs. This interorgan communication likely explains the coexistence of Alzheimer's disease and related dementias with cardiovascular and metabolic disorders characterized by overlapping pathophysiology. Skeletal muscle and the peripheral vasculature are key contributors to this and represent modifiable systems that can alter brain structure and function. Skeletal muscle regulates myokine release through motor neuron function, contractile activity, and metabolic perturbations, thereby influencing neuroplasticity, mitochondrial function, and inflammatory signaling, and may affect measures of peripheral vascular function, like reactive hyperemia. Other properties of the vasculature, including arterial stiffness, directly affect cerebral perfusion and blood-brain barrier permeability. These systems form a muscle-vascular-brain axis that contributes to brain health and impacts the risk of cognitive impairment. Therefore, our aim was to synthesize the current understanding of interactions among skeletal muscle, the peripheral vasculature, and the brain, and their collective role in maintaining cognitive health. We also highlight recent clinical trials and emerging strategies affecting interorgan cross talk. These conclusions support a model in which lifestyle interventions targeting peripheral systems, such as resistance training, may preserve brain health across all populations, offering scalable approaches applicable across the lifespan.
Maternal hyperglycemia, arising from pregestational or gestational diabetes, affects approximately 19% of pregnancies worldwide. Beyond its immediate obstetric and neonatal consequences, it may leave a durable imprint on vascular development. Within the framework of the Developmental Origins of Health and Disease hypothesis, this review synthesizes current evidence linking an intrauterine hyperglycemic environment to persistent vascular dysfunction in the offspring. The analysis first focuses on the utero-fetoplacental interface, where impaired spiral artery remodeling, abnormal placental angiogenesis, and weakened endothelial barrier integrity may disturb maternal-fetal exchange and expose developing tissues to early stress. Clinical and experimental data indicate that these disturbances are followed by long-term alterations in vascular structure and reactivity, including a shift toward a proconstrictor phenotype, endothelial dysfunction, reduced nitric oxide bioavailability, oxidative stress, altered cyclooxygenase-2-derived prostanoid signaling, and enhanced neurovascular sympathetic influences. Structural remodeling, particularly in resistance arteries, may further increase peripheral vascular resistance and favor the later development of hypertension. The review also considers how epigenetic changes, including DNA methylation and histone modifications, may contribute to a persistent molecular memory of fetal hyperglycemic exposure. By integrating evidence from placental biology, vascular reactivity, arterial remodeling, and early cardiovascular phenotypes, this review outlines how maternal hyperglycemia may shape offspring cardiovascular risk through sustained alterations in vascular structure and function.
Women with gestational diabetes mellitus (GDM) are more likely to develop cardiovascular disease (CVD) within 3 to 10 yr following pregnancy. Despite a return to normoglycemia shortly after gestation, GDM mothers still possess an increased risk of future CVD. In this study, we use a novel preclinical hormonal model of GDM to examine the mechanisms underlying future vascular and cardiac dysfunction in mothers with a history of GDM. We treated 16-wk-old pregnant C57BL/6J mice with the insulin receptor antagonist (S961; 30 nmol/kg sc) from gestational day 7 (second trimester of pregnancy) until delivery to induce GDM. GDM mice developed systolic and diastolic dysfunction, arterial stiffness, hypertension, increased cardiac mass, and exercise intolerance at 10 wk postpartum compared with saline-treated pregnant or S961-treated virgin mice. We also observed decreased plasma nitric oxide (NO) and increased endothelin-1 (ET-1) in GDM. The aorta of S961-induced GDM mice had increased pulse wave velocity, impaired vascular relaxation, remodeling, elevated reactive oxygen species (ROS) production and adhesion molecules, increased ET-1 type A receptor expression, and reduced sirtuin-1 (SIRT1) expression. The left ventricle of S961-induced GDM mice exhibited fibrosis, thickness, and increased ROS production. In addition, alterations in cardiac kinase activity in the nitric oxide/cyclic guanosine monophosphate/protein kinase G (NO/cGMP/PRKG) and AMP-activated protein kinase (AMPK) alpha pathways were observed at 10 wk postpartum using novel PamGene kinome technology. Thus, endothelin activation, suppressed NO/cGMP/PRKG signaling, impaired AMPK, and altered SIRT1 may be responsible for the development of vascular stiffness and cardiac dysfunction in mothers with a history of GDM.NEW & NOTEWORTHY Mechanisms underlying the future development of CVD in mothers with GDM were investigated using a mouse model of GDM that mimics the condition observed in human GDM. Examining the aorta in the later life of the GDM model reveals increased arterial stiffness and endothelin activation associated with vascular remodeling. In addition, kinome analysis reveals suppressed cardiac NO/cGMP/PRKG and impaired AMPK-SIRT1 signaling pathways, which corroborate the impaired ventricular relaxation observed in later life in GDM mothers.
Bronchopulmonary dysplasia (BPD) is characterized by disruption of newborn lung alveolar and vascular development. Administration of supplemental O2 predisposes to BPD by inducing oxidant stress in multiple subcellular compartments by augmenting reactive oxygen species (ROS) production. We studied the role of subcellular ROS in lung cyclic guanosine monophosphate (cGMP) signaling and its relationship to lung development in cells, embryonic lung explants, and newborn mice. Embryonic lung explants demonstrated increased mitochondrial ROS during hyperoxia. In hyperoxic human embryonic kidney 293T cells, ROS in the mitochondrial matrix, cytosol, and intermembrane space (IMS) increased. Those cells demonstrated impaired soluble guanylate cyclase (sGC)-cGMP responsiveness to a nitric oxide donor, a response prevented by the cytosolic glutathione mimetic ebselen as well as by the sGC activator, cinaciguat, but not by mitochondrial matrix-targeted ebselen or by expression of an H2O2 scavenger in the mitochondrial intermembrane space (IMS-Prdx5). Neonatal mice exposed to 75% O2 for 2 wk exhibited alveolar simplification and pulmonary artery wall thickening that were not rescued by cinaciguat or the sGC stimulator, riociguat. However, previous work demonstrated that mitochondria-targeted antioxidants prevent hyperoxia-mediated inhibition of lung alveolar development. Collectively, these studies demonstrate that separate mechanisms underlie the effects of hyperoxia on cGMP signaling and alveolarization in the newborn lung, with cytosolic oxidant stress responsible for impairing cGMP signaling and mitochondrial matrix ROS mediating the hyperoxia-induced impairment in lung alveolar development. Hence, the impairments in cGMP signaling and lung alveolar development during hyperoxia involve oxidant stress in distinct subcellular compartments and occur through independent mechanisms.NEW & NOTEWORTHY Hyperoxia impairs NO-mediated cGMP generation by augmenting cytosolic ROS. Cinaciguat rescued cGMP responsiveness in hyperoxic cells, hence oxidative damage to sGC is responsible. Increases in ROS in hyperoxic embryonic mouse lungs recapitulated responses previously recorded in adult mice. Hence, unlike premature infants, late gestational lung antioxidant maturation in the mouse is robust. Defects in lung alveolarization induced by hyperoxia were not rescued by cinaciguat or riociguat; hence, impaired cGMP signaling does not impair lung alveolarization.
