Nardone M, Thomas KN, Fan JL
… +2 more, Pugh GE, Fisher JP
Am J Physiol Heart Circ Physiol
· 2026 May · PMID 41875176
·
Publisher ↗
The effect of slow deep breathing (SDB) on the dynamic transduction of sympathetic nerve activity to the superficial femoral artery (SFA), femoral vein (FV), and blood pressure was determined. In 12 healthy volunteers (f...The effect of slow deep breathing (SDB) on the dynamic transduction of sympathetic nerve activity to the superficial femoral artery (SFA), femoral vein (FV), and blood pressure was determined. In 12 healthy volunteers (five women, 25 ± 7 yr, means ± SD), simultaneous imaging of the SFA and FV, along with contemporary measures of muscle sympathetic nerve activity (MSNA), was obtained and signal-averaging techniques were used to quantify sympathetic neurovascular transduction at rest (baseline) and during 5 min SDB at 6 breaths/min. At baseline, MSNA bursts were followed by transient increases in mean arterial pressure (MAP; peak +3.0 ± 1.2 mmHg), decreases in SFA flow (nadir -6.3 ± 4.5 mL/min), and small, inconsistent increases in FV flow (peak +4.3 ± 6.7 mL/min). SDB decreased MSNA burst frequency and burst incidence by ∼30%, whereas MAP was unchanged. During SDB, MSNA bursts were followed by greater increases in MAP (peak +6.0 ± 2.4 mmHg, < 0.001 vs. baseline), greater decreases in SFA flow (nadir -9.8 ± 4.0 mL/min, = 0.002 vs. baseline), and a tendency for a greater increase in FV flow (peak +20.6 ± 21.0 mL/min, = 0.051). Therefore, although SDB reduces MSNA, the augmented MSNA transduction to blood pressure may help to preserve MAP. SDB evoked greater reductions in SFA flow and increases in FV flow following an MSNA burst, which may work synergistically with the respiratory muscle pump to facilitate venous return. Collectively, these findings highlight the important role played by MSNA in the dynamic regulation of peripheral blood flow, venous return, and blood pressure. Sympathetic neurovascular transduction to mean arterial pressure (MAP), superficial femoral artery (SFA), and femoral vein (FV) flow were quantified at baseline and during slow deep breathing (SDB). MAP was unchanged during SDB, whereas MSNA was decreased, and sympathetic transduction to MAP, SFA flow, and FV flow (tendency) were increased. Respiratory-coupled oscillations in MSNA, SFA flow, and FV flow appear to work synergistically with the respiratory muscle pump to facilitate venous return during SDB.
Trampel KA, Gross KY, O'Reilly D
… +7 more, Melisova A, Salman B, Green S, George SA, Khvorova A, Efimov IR, Efimova T
Am J Physiol Heart Circ Physiol
· 2026 May · PMID 41874387
·
Publisher ↗
The anthracycline antibiotic doxorubicin (DOX) is a potent chemotherapy drug, but its use is limited by dose-dependent cardiotoxicity. We previously reported that genetic deletion of p38δ protects female mice from DOX-in...The anthracycline antibiotic doxorubicin (DOX) is a potent chemotherapy drug, but its use is limited by dose-dependent cardiotoxicity. We previously reported that genetic deletion of p38δ protects female mice from DOX-induced cardiotoxicity (DIC), suggesting that inhibiting this kinase could be an effective treatment. Here, we developed a fully chemically stabilized small interfering RNA (siRNA) that effectively silences p38δ. In an acute DIC model, silencing p38δ reduced mortality and morbidity, preserved heart structure and function, and decreased fibrosis in female mice. It also alleviated DOX-induced electrophysiological remodeling and decreased cardiac inflammation and senescence-associated secretory phenotype (SASP). Transcriptomic analysis of DOX-treated p38δ-deficient hearts revealed the downregulation of genes associated with inflammation, ion transport, and impulse generation, and the upregulation of genes involved in oxidative stress management, autophagy, and immune signaling. These findings support silencing p38δ as a promising approach to protect against DIC, highlighting the potential of siRNA-based therapies to mitigate anthracycline cardiotoxicity. This study presents the first isoform-specific inhibition of p38δ using a docosanoic (DCA)-conjugated, fully chemically stabilized siRNA. Our lead compound, si644, achieves potent, durable, and well-tolerated p38δ silencing in vivo in mouse hearts and ex vivo in human cardiac organotypic slices. si644-mediated p38δ silencing protects female mice from DIC by mitigating DOX-induced structural, electrophysiological, fibrotic, and inflammatory remodeling. These findings establish p38δ inhibition as a promising therapeutic strategy for preventing anthracycline cardiotoxicity.
Wu LH, Yang J, Pakkiri LS
… +11 more, Monteiro LJ, Peñailillo R, Lim PL, Choolani MA, Kemp MW, Li LJ, Cantin C, Valenzuela I, Leiva A, Drum CL, Illanes SE
Am J Physiol Heart Circ Physiol
· 2026 May · PMID 41870028
·
Publisher ↗
The developmental origins of health and disease (DOHaD) hypothesis links intrauterine exposure to suboptimal fetal development and later-life cardiometabolic health. In 56 mother-newborn pairs, we quantified 389 newborn...The developmental origins of health and disease (DOHaD) hypothesis links intrauterine exposure to suboptimal fetal development and later-life cardiometabolic health. In 56 mother-newborn pairs, we quantified 389 newborn cord blood metabolites by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and recorded 24 clinical variables. With weighted coexpression network analysis, we identified , comprising birth weight and metabolites enriched for the "gut-liver indole metabolism" pathway (indole, indole-3-pyruvic acid, and indole-3-lactic acid). Multivariable regression revealed that each 1-SD higher expression score was associated with -0.26 [95% confidence interval (CI): -0.51, -0.01]-SD lower 3rd-trimester total cholesterol ( = 0.039), adjusting for newborn and maternal covariates. This supports a coordinated newborn pattern of lower birth weight and lower cord blood indole metabolite abundance in pregnancy cases with higher late-pregnancy total cholesterol. Stratified analyses further suggested that, among pregnancies with maternal supraphysiological hypercholesterolemia (MSPH; 3rd-trimester total cholesterol ≥ 280 mg/dL), higher maternal age and higher 1st-trimester systolic blood pressure were accompanied by lower score, whereas these associations were not observed in non-MSPH pregnancies. Complementary regression analysis associated each tertile higher cord blood indole-3-propionic acid (IPA) with -9.09 [-17.45, -0.72]-mg/dL lower 1st-trimester cholesterol ( = 0.038). Separately, each 1-tertile higher IPA was linked to 192.22 [55.44, 329.00]-g higher newborn weight ( = 0.008). Both 1st- and 3rd-trimester total cholesterols were positively associated with higher cord blood oxidative stress (8-hydroxy-2'-deoxyguanosine, 8-OHdG). In conclusion, maternal cholesterol level varies with cord blood indole metabolites and birth weight, suggesting a potential shared metabolic axis modifiable by maternal cholesterol level in mother-newborn pairs. This study identifies a coexpression network module connecting birth weight with cord blood indole metabolites, highlighting an integrated neonatal growth-metabolism signature. Maternal lipid status tracks with this signature, adding molecular resolution to the developmental origins of health and disease (DOHaD) paradigm by implicating growth-linked biochemical perturbations in gut-derived indole metabolites. Given the established relevance of indole metabolites to cardiovascular health, our preliminary results motivate future studies aimed at targeting neonatal metabolism as an early window for cardiovascular health intervention.
"Athlete's heart" is well-documented in males, but female-specific data remain limited despite increasing participation in women's sport. This systematic review examined studies investigating exercise-induced cardiac ada..."Athlete's heart" is well-documented in males, but female-specific data remain limited despite increasing participation in women's sport. This systematic review examined studies investigating exercise-induced cardiac adaptation, auditing female athlete representation and methodological quality using a standardized framework. A total of 767 articles met inclusion, comprising 94,744 participants. Male-only cohorts made up 54% of studies ( = 416), whereas female-only studies represented just 5% ( = 38). Only 7% ( = 56) of studies included a male-female subanalysis, whereas 3% of studies ( = 21) used direct sex-comparative design. Notably, 6% of studies ( = 44) did not report participant sex at all. Females accounted for less than one quarter of the total sample (24%, = 23,061 participants). Football (soccer) was the most represented sport overall ( = 13,582 participants) and in male-only studies ( = 5,242 participants). Basketball was the most common in female-only studies ( = 314 participants). Ethnicity was reported in 17% of studies ( = 127; 43,683 participants), with 80% of participants identified as White and 16% as African/Afro-Caribbean. Para-athletes comprised 0.4% of the total cohort. Echocardiography was the predominant imaging modality (88%), with 97% of studies reporting left ventricular parameters. Only 10 studies (3% of those including females) provided sufficient information to classify menstrual status, and none met best-practice recommendations. These findings highlight the need to prioritize diverse female athlete cohorts, including para-athletes, broader ethnic representation, and wider range of sport domains, to enable accurate clinical interpretation and equitable cardiovascular assessment in women.
Nesci A, Scagliusi A, Ruggieri V
… +10 more, Ponziani FR, Parati EA, Trivelloni P, Lucertini M, Santoro L, Di Giorgio A, D'Alessandro A, Carnuccio C, Perelli P, Santoliquido A
Am J Physiol Heart Circ Physiol
· 2026 May · PMID 41855027
·
Publisher ↗
High-performance fighter pilots are routinely subjected to extreme mechanical and physiological stressors, including exposure to high +Gz accelerations that may impact vascular health. In this short report, we evaluated...High-performance fighter pilots are routinely subjected to extreme mechanical and physiological stressors, including exposure to high +Gz accelerations that may impact vascular health. In this short report, we evaluated endothelial function in 20 Eurofighter Typhoon (F-2000A) pilots and 19 matched control pilots flying nonhigh-G aircraft (KC-767A). Flow-mediated dilation (FMD) of the brachial artery was measured before and after flight sorties to assess vascular response. FMD values were lower after flight compared with preflight measurements, reflecting a significant main effect of time across the entire cohort ( < 0.05). Within-group analyses revealed a larger absolute reduction in FMD in F-2000A pilots (median = 10.02%-6.45%) compared with controls (9.40%-8.80%). However, the absence of a significant time × group interaction indicates that this response was not statistically different between pilot groups. In addition, F-2000A pilots exhibited smaller arterial diameters at rest and a significant postflight increase in baseline vessel caliber (3.81-4.13 mm; < 0.001), suggesting a transient vasodilatory response potentially related to thermal or hemodynamic stress. These findings suggest an acute endothelial response to the high-performance flight environment. This study underscores the need for continued cardiovascular surveillance in high-performance aviators and supports further investigation of FMD as a noninvasive marker of vascular function within structured aeromedical follow-up programs. This study is the first to evaluate endothelial function in fighter pilots exposed to high Gz (up to +9). Results indicate a postflight reduction in flow-mediated dilation (FMD) and time-dependent vascular changes associated with high-performance flight exposure. These findings highlight the potential value of FMD as a noninvasive tool for monitoring cardiovascular health and developing targeted aeromedical follow-up strategies for high-performance aircrew.
Heinen A, Spychala A, Ballmann L
… +9 more, Gödecke S, Faradj Z, Bresch F, Krüger M, Bottermann K, Zabri H, Fischer J, Petzsch P, Gödecke A
Am J Physiol Heart Circ Physiol
· 2026 May · PMID 41850047
·
Publisher ↗
Diabetes is associated with an increased incidence of heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms are poorly understood. A shortage of mouse models reflecting the diverse HFpEF p...Diabetes is associated with an increased incidence of heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms are poorly understood. A shortage of mouse models reflecting the diverse HFpEF pathophysiology contributes to this inadequate understanding of disease mechanisms. We conducted a comprehensive analysis of a nongenetic, inducible type 2 diabetes mellitus (T2DM) mouse model about its suitability as a preclinical model of cardiometabolic, diabetes-induced HFpEF. T2DM was induced in C57Bl/6 mice by a high-fat/high-sucrose diet and a low-dose streptozotocin (DIO-STZ). Cardiac function was assessed in vivo by echocardiography and left ventricular catheterization and in vitro using the isolated perfused heart. Structural, molecular, and bioenergetic disturbances were analyzed by immunohistochemistry, RNA-seq, qPCR, Western blot, and extracellular flux analysis of myocardial tissue. Blood glucose, fatty acids, and ketone body levels were elevated, and insulin levels were reduced in DIO-STZ compared with chow. DIO-STZ mice showed an HFpEF phenotype with reduced cardiac output, end-diastolic volume, and increased filling pressure. No differences in myocardial fibrosis or in vitro stiffness were detected between DIO-STZ and chow. RNA-Seq pointed toward disturbances in lipid and ketone metabolism. Extracellular flux analysis revealed increased fatty acid oxidation capacity without differences in glucose metabolism. No general mitochondrial dysfunction was observed, but a reduced capacity for β-hydroxybutyrate oxidation. The diabetic DIO-STZ mouse model showed a pronounced functional HFpEF phenotype with underlying mechanisms that remarkably differ from other HFpEF models, making the DIO-STZ model a relevant extension of the range of HFpEF mouse models, especially for investigating molecular mechanisms or therapeutic interventions in diabetes-associated HFpEF. Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome whose pathophysiological mechanisms are incompletely understood, potentially due to a lack of preclinical models reflecting the broad range of pathophysiological aspects. We describe a diabetic DIO-STZ mouse model showing a pronounced HFpEF with underlying mechanisms that remarkably differ from other HFpEF models, making this model a relevant extension of the range of HFpEF models, especially for investigating molecular mechanisms or therapeutical interventions in diabetes.
Postmenopause is associated with increased adiposity, metabolic syndrome, and heightened cardiovascular disease (CVD) risk, yet the adipose-derived factors potentially contributing to vascular impairment remain poorly de...Postmenopause is associated with increased adiposity, metabolic syndrome, and heightened cardiovascular disease (CVD) risk, yet the adipose-derived factors potentially contributing to vascular impairment remain poorly defined. Asprosin, a glucogenic adipokine secreted by white adipose tissue (WAT), is elevated in metabolic diseases; however, its association with postmenopausal vascular complications remains unknown. In this study, we investigated circulating and adipose tissue asprosin levels in a long-term ovariectomy (OVX) mouse model of postmenopause. Female mice underwent OVX or sham surgery and were followed for 20 wk. OVX mice developed typical postmenopausal bone porosity, specifically in the lumbar vertebrae, along with cardiometabolic disorders, including weight gain, increased adiposity, metabolic syndrome-like alterations, and significant arterial stiffness, an early vascular insult marker. Notably, these postmenopausal changes were associated with elevated circulating asprosin levels and increased asprosin expression in subcutaneous adipose tissue. Results from ex vivo wire myography studies demonstrated that asprosin directly potentiates vasoconstriction, implying that asprosin exerts a direct vascular effect. Together, these findings provide novel evidence of an association between elevated asprosin and postmenopausal vasculometabolic alterations. These observations support further investigation of asprosin as a potential biomarker of cardiometabolic and vascular changes and as a candidate for future investigation. Postmenopause is a critical period in women's lives marked by metabolic and vascular changes that remain poorly understood. Asprosin, a novel adipokine, is linked to metabolic disorders and cardiovascular risk. In long-term OVX mice, circulating asprosin levels were elevated and associated with weight gain and arterial stiffness. Exogenous asprosin was associated with vasoconstriction, supporting its potential as a biomarker and a candidate for further mechanistic investigation in postmenopausal vasculometabolic regulation.
Am J Physiol Heart Circ Physiol
· 2026 May · PMID 41843908
·
Publisher ↗
Pregnancy and lactation increase cardiovascular demand and may unmask postpartum cardiac vulnerability under metabolic stress. We tested whether exposure to a high-fat/high-sucrose (HFHS) diet from premating through lact...Pregnancy and lactation increase cardiovascular demand and may unmask postpartum cardiac vulnerability under metabolic stress. We tested whether exposure to a high-fat/high-sucrose (HFHS) diet from premating through lactation induces postpartum hemodynamic dysfunction with preserved ejection fraction (EF) and whether voluntary wheel running mitigates these alterations. Virgin C57BL/6J female mice were assigned to control sedentary (CS), HFHS sedentary (HS), or HFHS with voluntary wheel running across the reproductive window. Left ventricular (LV) pressure-volume (P-V) analysis was performed 6-9 days after weaning at baseline and during dobutamine challenge to assess β-adrenergic reserve. Despite preserved EF, HS dams exhibited reduced end-diastolic volume (EDV) and impaired forward performance [lower stroke volume (SV), cardiac output, and stroke work] accompanied by higher filling pressure, increased diastolic stiffness (end-diastolic elastance, ), impaired ventricular-arterial coupling (/), and reduced load-independent contractility [end-systolic elastance ()]. Dobutamine increased chronotropic and inotropic indices across groups; however, HS remained lower than CS during dobutamine for SV and , indicating limited capacity to augment performance under stress. In contrast, wheel running improved intrinsic contractility and maintained at rest and during dobutamine without differences in body or heart weight. These findings indicate that HFHS exposure across pregnancy and lactation is associated with postpartum hemodynamic dysfunction characterized by preserved EF with impaired filling, increased diastolic stiffness, and reduced reserve; voluntary wheel running across this window mitigates key abnormalities in systolic mechanics and ventricular-arterial coupling. HFHS exposure across pregnancy and lactation produces postpartum hemodynamic dysfunction with preserved EF, marked by higher filling pressure, increased diastolic stiffness, and impaired ventricular-arterial coupling and β-adrenergic reserve. Voluntary wheel running from premating through lactation improves intrinsic contractility and preserves coupling during dobutamine challenge.
Milrinone, a phosphodiesterase III inhibitor, exerts positive inotropic and vasodilatory effects via cyclic adenosine monophosphate-mediated signaling pathways. However, its comprehensive hemodynamic impact, particularly...Milrinone, a phosphodiesterase III inhibitor, exerts positive inotropic and vasodilatory effects via cyclic adenosine monophosphate-mediated signaling pathways. However, its comprehensive hemodynamic impact, particularly on venous return, remains incompletely characterized. Using the generalized circulatory equilibrium framework, we investigated the cardiovascular effects of milrinone in normal and heart failure (HF) canine models. Ten beagle dogs (5 normal, 5 with acute left HF induced by left coronary microembolization) were studied under general anesthesia and open-chest conditions. Milrinone was administered intravenously at 0.5 µg·kg·min. From the circulatory equilibrium framework, we derived the effective stressed blood volume (SBV) and the logarithmic slope (SL) of the left ventricular (LV) output curve, which indicates LV pumping capability. Milrinone infusion reduced SBV from 31.6 ± 1.3 to 26.5 ± 1.7 mL/kg in the normal model and from 35.7 ± 3.0 to 32.1 ± 3.6 mL/kg in the HF model, with a significant main effect of drug ( = 0.004) but no model × drug interaction in two-way ANOVA ( = 0.531). In the normal group, SL was unchanged [61.6 ± 1.6 to 62.2 ± 3.5 mL·min·kg], resulting in decreases in aortic pressure (AP) and cardiac output (CO). In contrast, in the HF group, milrinone increased SL [18.3 ± 3.1 to 30.2 ± 4.3 mL·min·kg], with a significant model × drug interaction ( = 0.044). As a result, AP and CO were preserved, while left atrial pressure was reduced. In conclusion, in the HF canine model, milrinone improves the circulatory equilibrium point by enhancing LV pumping function and reducing SBV. Analysis using a generalized circulatory equilibrium framework demonstrates that milrinone reduces stressed blood volume, shifting the venous return curve downward in both normal and heart failure (HF) models. In contrast, milrinone shifts the cardiac output (CO) curve upward only in the HF model. Left atrial pressure is reduced without CO reduction in the HF model, whereas CO decreases in the normal model. These findings indicate that circulatory equilibrium responses to milrinone depend on cardiac function.
Gotschy A, Binter C, Schlenker R
… +3 more, Tanner FC, Manka R, Kozerke S
Am J Physiol Heart Circ Physiol
· 2026 May · PMID 41830470
·
Publisher ↗
Aortic stenosis (AS) induces complex alterations in ascending aortic flow, including increased turbulent kinetic energy (TKE), altered velocity profiles, and changes in flow organization, which can be quantified using fo...Aortic stenosis (AS) induces complex alterations in ascending aortic flow, including increased turbulent kinetic energy (TKE), altered velocity profiles, and changes in flow organization, which can be quantified using four-dimensional (4D) flow cardiovascular magnetic resonance (CMR). The physiological relevance of these flow-derived parameters with respect to left ventricular (LV) adaptation remains incompletely understood. We investigated the associations between 4D flow CMR-derived hemodynamic metrics and established markers of LV decompensation and remodeling in patients with AS. Fifty-nine patients with AS (70 ± 14 yr) underwent 4D flow CMR using a Bayesian multipoint phase-contrast sequence with k-t PCA acceleration and three velocity-encoding steps in each direction. Quantified parameters included peak TKE, stroke volume-normalized systolic TKE (normalized TKE), peak velocity, jet angle, relative flow displacement, and mean helicity. Associations with NT-proBNP and indexed LV mass were analyzed. Peak TKE, normalized TKE, and peak systolic velocity were significantly associated with both indexed LV mass and NT-proBNP, whereas mean helicity was associated with indexed LV mass only. In contrast, jet angle and flow displacement showed no relationship with either marker of LV decompensation and remodeling. During long-term follow-up, no 4D flow CMR parameter was associated with adverse clinical events, likely due to timely valve replacement in most patients. In conclusion, these findings indicate that flow energetics-particularly TKE and peak systolic velocity-most closely capture the hemodynamic burden imposed on the LV supporting their physiological relevance in AS. Isolated descriptors of flow geometry, in contrast, have not shown to reflect maladaptive LV remodeling. This study used advanced four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) to investigate alterations in aortic flow of patients with aortic stenosis and its relation to left ventricular remodeling and decompensation. It shows that turbulent kinetic energy, which is a measure of irreversible energy loss downstream of a stenotic valve, and peak flow velocity are the characteristics, which best capture the hemodynamic burden imposed on the left ventricle (LV). In contrast, geometric flow descriptors such as jet angle and flow displacement lacked physiological relevance.
Sandstedt M, Johansson M, Jonsson M
… +9 more, Vukusic K, Ulfenborg B, Sandstedt M, Mattsson Hultén L, Rotter Sopasakis V, Dellgren G, Jeppsson A, Synnergren J, Sandstedt J
Am J Physiol Heart Circ Physiol
· 2026 May · PMID 41830467
·
Publisher ↗
Intracardiac mast cells (CMCs) have previously been shown to contribute to adverse remodeling and heart failure in animal models. As CMCs in human hearts remain unexplored, the aim of this study was to investigate the pa...Intracardiac mast cells (CMCs) have previously been shown to contribute to adverse remodeling and heart failure in animal models. As CMCs in human hearts remain unexplored, the aim of this study was to investigate the pathophysiological relevance of human CMCs through transcriptomic profiling. Biopsies were collected from the four heart chambers of heart failure patients undergoing heart transplantation surgery ( = 9), as well as from deceased organ donors without chronic heart failure ( = 5). Using flow cytometry, C-kitCD45 CMCs and C-kitCD45 hematopoietic cells were identified in all failing and nonfailing hearts and were sorted for RNA sequencing analysis. In comparison with other hematopoietic C-kitCD45 cells and CMCs in nonfailing hearts, CMCs in failing hearts demonstrated significant activation of pathways involved in cardiac remodeling and heart failure, including fibrosis-associated and inflammatory pathways. Our results support a role for mast cells in human heart failure and constitute the first in-depth characterization of mast cells in the nonfailing and failing human heart. Intracardiac mast cells (CMCs) have been shown to contribute to remodeling and fibrosis in animal models. No phenotypical characterization of human CMCs has been conducted before the current transcriptomic profiling study. CMCs isolated from failing human hearts demonstrated activated pathways involved in cardiac remodeling and fibrosis, both compared with other hematopoietic cells and to CMCs in nonfailing hearts. The study suggests that CMCs may constitute a novel candidate for modulation in human heart failure.
Sharma N, Huang Y, Jia G
… +3 more, Martinez-Lemus LA, Padilla J, Manrique-Acevedo C
Am J Physiol Heart Circ Physiol
· 2026 Apr · PMID 41830462
·
Full text
Abdominal aortic aneurysm (AAA), a pathological dilatation of the abdominal aorta, is primarily driven by chronic inflammation of the aortic wall. Although estrogen is known to exert protective anti-inflammatory effects...Abdominal aortic aneurysm (AAA), a pathological dilatation of the abdominal aorta, is primarily driven by chronic inflammation of the aortic wall. Although estrogen is known to exert protective anti-inflammatory effects in AAA, the role of endothelial estrogen receptor alpha (ERα) signaling in AAA pathogenesis remains unclear. We investigated the vasoprotective role of endothelial ERα using endothelial cell (EC)-specific ERα knockout (eERαKO) mice subjected to a beta-aminopropionitrile plus angiotensin II model of AAA. eERα deficiency significantly accelerated AAA formation in male mice, evidenced by increased maximal aortic diameter, worsened medial elastin degradation, increased collagen deposition, and upregulated macrophage infiltration, whereas female mice were largely unaffected. Mechanistically, loss of endothelial ERα was associated with elevated endothelin-1 (ET-1) expression in aortic tissue. In vitro, pharmacological inhibition of ERα with methyl-piperidino-pyrazole increased endothelial ET-1 secretion and increased monocyte adhesion in EC-monocyte coculture assays. Collectively, these findings reveal that endothelial ERα constrains AAA development in male mice, possibly by suppressing ET-1-mediated endothelial activation and macrophage recruitment. This work highlights a protective role of endothelial ERα signaling in maintaining aortic structural integrity and preventing aneurysmal disease. We identify an important role of endothelial estrogen receptor alpha (ERα) in a sex-dependent regulation of abdominal aortic aneurysm formation. Using mice with endothelial cell-specific deletion of ERα, we found that loss of endothelial ERα signaling exacerbates aneurysm development in male mice, associated with increased macrophage infiltration and elevated endothelin-1 expression. These findings reveal a previously unrecognized endothelial-specific mechanism by which estrogen signaling preserves aortic wall integrity and suppresses inflammatory vascular remodeling.
Am J Physiol Heart Circ Physiol
· 2026 May · PMID 41818164
·
Full text
Cardiosphere-derived cells (CDCs) and the nonsteroidal aldosterone antagonist finerenone can each reduce myocardial fibrosis and have emerged as potential therapeutics for heart failure with preserved ejection fraction (...Cardiosphere-derived cells (CDCs) and the nonsteroidal aldosterone antagonist finerenone can each reduce myocardial fibrosis and have emerged as potential therapeutics for heart failure with preserved ejection fraction (HFpEF). Although these interventions can improve diastolic properties, their direct effects on left ventricular (LV) chamber stiffness have not been established. Accordingly, we examined their effect in swine with increased LV chamber stiffness and fibrosis from repetitive pressure overload (RPO). Swine ( = 19) were subjected to daily (1 h) episodes of RPO for 2 wk using phenylephrine to transiently elevate left ventricular end-diastolic volume (LVEDP) to ∼30 mmHg. After 2 wk, RPO was discontinued, and animals received intracoronary saline ( = 6), allogeneic CDCs (30 × 10, = 7), or oral finerenone (20 mg/day; = 6) and were followed for 4 wk. LV end-diastolic pressure and end-diastolic volume index were measured at normal and elevated preload to assess LV chamber stiffness (ΔLVEDP/ΔLVEDVi), and postmortem picrosirius red staining was performed to quantify interstitial fibrosis. Four weeks after cessation of RPO, saline-treated swine demonstrated sustained increases in LV chamber stiffness (1.7 ± 0.3 mmHg/mL/m vs. 0.6 ± 0.1 mmHg/mL/m in controls, < 0.01). This was associated with increased fibrosis (8.5 ± 0.7% vs. 6.7 ± 0.4% in controls, < 0.05) that decreased after treatment with CDCs (6.1 ± 0.5%, < 0.05) and finerenone (5.4 ± 0.6%, < 0.05). Despite these antifibrotic effects, LV chamber stiffness remained elevated after both agents (CDCs: 1.9 ± 0.4 mmHg/mL/m; finerenone: 1.4 ± 0.3 mmHg/mL/m, both < 0.05 vs. normal controls). Although both CDCs and finerenone reduced fibrosis, these changes were not associated with reductions in LV chamber stiffness. Additional mechanisms likely underlie increased LV chamber stiffness in this model, which may have relevance to the therapeutic impact of these interventions on diastolic function in HFpEF. Swine with increased left ventricular (LV) chamber stiffness and fibrosis from 2 wk of repetitive pressure overload demonstrated discordant effects following two disparate antifibrotic interventions. A single infusion of intracoronary allogeneic cardiosphere-derived cells and 4 wk of oral finerenone each effectively reduced myocardial interstitial fibrosis. Despite reversal of fibrosis, LV chamber stiffness did not improve with either intervention, suggesting that myocyte-dependent mechanisms may play an important role in diastolic dysfunction from intermittent hemodynamic overload.
Padilla J, Ramirez-Perez FI, Smith JA
… +6 more, Soares RN, Burken M, Uptergrove E, Lee S, Martinez-Lemus LA, Manrique-Acevedo C
Am J Physiol Heart Circ Physiol
· 2026 Apr · PMID 41818160
·
Full text
Obesity and insulin resistance promote arterial stiffening and hypertension, increasing cardiovascular risk. Activation of the epithelial sodium channel (ENAC) contributes to vascular stiffening in preclinical models, bu...Obesity and insulin resistance promote arterial stiffening and hypertension, increasing cardiovascular risk. Activation of the epithelial sodium channel (ENAC) contributes to vascular stiffening in preclinical models, but the vascular effects of ENAC inhibition in adults with obesity and insulin resistance are not well defined. In this phase II, 24-wk, randomized, double-blind, single-center, placebo-controlled trial, 137 adults aged 30-70 yr with overweight or obesity and at least one metabolic syndrome feature were randomized (2:1) to the ENAC inhibitor amiloride (5 mg daily) or placebo. Carotid-femoral pulse wave velocity (cfPWV), blood pressure, and vascular function were assessed at baseline, 12 wk, and 24 wk. Amiloride significantly reduced arterial stiffness, with decreases in cfPWV at 12 and 24 wk, whereas no changes were observed with placebo. Systolic blood pressure was also reduced, with a mean reduction of 5.6 mmHg at 24 wk. Older age was associated with greater reductions in cfPWV and systolic blood pressure. Amiloride increased serum potassium and lowered fasting glucose, but did not significantly affect brachial artery flow-mediated dilation. No severe adverse events were observed. In conclusion, low-dose amiloride improves blood pressure and arterial stiffness in adults with overweight or obesity and features of metabolic syndrome, without major safety concerns. These findings suggest that blood pressure lowering with amiloride is associated with favorable changes in vascular stiffness in this population. Obesity and insulin resistance accelerate arterial stiffening and hypertension, increasing cardiovascular risk. Activation of the epithelial sodium channel (ENAC) contributes to vascular stiffening in preclinical models, yet the vascular effects of ENAC inhibition in adults with obesity and insulin resistance remain poorly characterized. Here, we demonstrate that low-dose amiloride reduces blood pressure and improves arterial stiffness in adults with overweight or obesity and features of metabolic syndrome, without major safety concerns.