Izaias JE, Ono BE, Sales AO
… +22 more, Rodrigues TS, Silva GMPS, Lima RF, Nunes CS, Bittencourt MA, Pentagna PS, Salemi VMC, Consolim-Colombo FM, Irigoyen MCC, Rodrigues AG, Negrão CE, Testa L, De Angelis K, Porcari AM, Rocha HNM, Teixeira GF, Rocha NG, da Nóbrega ACL, Craighead DH, Clayton ZS, Moll-Bernardes RJ, Sales ARK
Am J Physiol Heart Circ Physiol
· 2026 Jun · PMID 42089906
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Previous studies have reported blunted increases in blood pressure during physical exercise in cancer survivors treated with cardiotoxic chemotherapy. However, the sympathetic neural mechanisms underlying this attenuated...Previous studies have reported blunted increases in blood pressure during physical exercise in cancer survivors treated with cardiotoxic chemotherapy. However, the sympathetic neural mechanisms underlying this attenuated response remain unknown. We hypothesized that long-term breast cancer (BC) survivors exhibit impaired muscle metaboreflex function, which would partially explain the reduced sympathetic cardiovascular responses to exercise. Nineteen BC survivors [age 49 ± 2 yr; body mass index (BMI) 27 ± 1 kg/m] and 14 sex-, age-, and BMI-matched controls (age 48 ± 2 yr; BMI 26 ± 1 kg/m) were studied. Muscle sympathetic nerve activity (MSNA; microneurography), mean arterial pressure (MAP; Finometer), stroke volume, cardiac output, and total peripheral resistance (SV, CO, and TPR; Modelflow), and heart rate [HR; electrocardiogram (ECG)] were continually measured at baseline, during 3 min of static handgrip (HG) at 30% maximal voluntary contraction, followed by postexercise ischemia (PEI) to isolate muscle metaboreflex activation. BC survivors were evaluated ∼9 yr after treatment completion. Changes in MAP during HG were attenuated in BC survivors versus controls, and this difference persisted during PEI (Δ12.0 ± 2.0 mmHg vs. 21.0 ± 2.0 mmHg; = 0.001). Similarly, the MSNA burst frequency response to HG was lower in BC survivors than controls, and the difference remained during PEI (Δ3.0 ± 1.0 bursts/min vs. 9.0 ± 1.0 bursts/min; = 0.001). SV and CO were reduced during HG in BC survivors ( < 0.05) but not during PEI. No group differences were observed in HR or TPR. Collectively, these findings indicate that the attenuated pressor and sympathetic neural responses to exercise in long-term BC survivors are explained, at least in part, by attenuated muscle metaboreflex control. Long-term breast cancer (BC) survivors previously treated with doxorubicin- and trastuzumab-based chemotherapy show reduced muscle metaboreflex activation, which partly explains attenuated pressor and sympathetic neural responses to exercise in this population. Importantly, these findings shed light on the blunted exercise-induced blood pressure increase observed in long-term BC survivors.
Saffold K, Tall A, Lowery AT
… +4 more, Pryor T, Jones-Muhammad M, Shao Q, Warrington JP
Am J Physiol Heart Circ Physiol
· 2026 Jun · PMID 42083975
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Preeclampsia is a pregnancy complication characterized by high blood pressure and signs of organ damage, after the 20th week of pregnancy. Children born to mothers with preeclampsia or eclampsia (new-onset seizures durin...Preeclampsia is a pregnancy complication characterized by high blood pressure and signs of organ damage, after the 20th week of pregnancy. Children born to mothers with preeclampsia or eclampsia (new-onset seizures during pregnancy) are more likely to develop learning and memory deficits and are more susceptible to neurovascular diseases compared with those born from normal pregnancies. The contributing mechanisms are unknown. In this study, we assessed whether exposure to reduced uteroplacental perfusion (RUPP), modeling placental hypoperfusion and preeclampsia, with or without pentylenetetrazol (PTZ) injection (to induce seizures and model eclampsia), results in cognitive impairment, Alzheimer's disease markers, and regional cerebral perfusion changes in adult offspring. On (), pregnant C57BL/6 mice ( = 22) underwent Sham or RUPP surgery followed by injection or no treatment with PTZ (40 mg/kg) on GD18.5. At 2 mo of age, spatial learning and cerebral perfusion were measured in randomly selected offspring or averaged to obtain mean data per sex, per litter ( = 4-6 data points per group/treatment). RUPP-exposed offspring took a longer distance and made more errors navigating the Barnes maze. Cerebral perfusion was reduced in offspring exposed to RUPP, specifically in the prefrontal cortex, superior sagittal sinus, and whole brain. There was a significant reduction in perfusion in seizure-exposed offspring in the superior sagittal and transverse sinuses, whole brain, and cerebellum. Our results support the hypothesis that exposure to preeclampsia/eclampsia-like symptoms leads to mild learning impairment through reduced cerebral perfusion to cortical regions and decreased drainage of waste from the brain via the cerebral sinuses. This is the first study to assess vascular-related cognitive function and Alzheimer's disease markers in young adult mice exposed to preclinical preeclampsia and eclampsia-like conditions. We show that mild learning impairments occur in the presence of cerebral hypoperfusion and reduced venous drainage into the brain sinuses. We also report that as early as 2 mo of age, Alzheimer's disease markers are increased in the brains of offspring exposed to seizures.
Mohammed ASA, Demeter-Haludka V, Abdelmagid AAE
… +16 more, Topal L, Muhammad N, Mohácsi G, Paskuj B, Bitay G, Kohajda Z, Benke K, Sayour AA, Radovits T, Bitay M, Virág L, Jost N, Baczkó I, Varró A, Merkely B, Nagy N
Am J Physiol Heart Circ Physiol
· 2026 Jun · PMID 42065613
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Chronic heart failure constitutes a clinical syndrome characterized by substantial attenuation of repolarization reserve resulting from electrical remodeling. The small-conductance Ca-activated K channel (SK) has been re...Chronic heart failure constitutes a clinical syndrome characterized by substantial attenuation of repolarization reserve resulting from electrical remodeling. The small-conductance Ca-activated K channel (SK) has been reported to undergo upregulation in animal heart failure models and in human preparations; however, its exact function is not fully understood. This study aims to elucidate the functional role of SK channels in end-stage human heart failure. SK-protein expression of undiseased and failed human ventricular tissue was investigated by Western blot technique. Action potentials were measured by the standard microelectrode technique from right ventricular papillary muscles of undiseased hearts and from right and left papillary muscles and from left midmyocardial tissue slices of failing hearts. Ionic currents were recorded by the whole cell configuration of the patch-clamp technique on isolated cells obtained from left ventricles of failing hearts. Failing hearts exerted consistent action potential lengthening and lacked spike-and-dome compared with undiseased hearts. Western blot revealed identical SK expression between undiseased and failing hearts. Apamin (100 nM), a commonly used selective SK channel inhibitor, failed to alter action potential duration values of the failing hearts in left and right endocardial preparations and in left midmyocardium. Furthermore, no apamin-sensitive current was identified in isolated cells. Week coupling between SK2 channels and L-type Ca channels was found. These results do not confirm the results of previous studies claiming an important role of SK channels in the repolarization of the human failing heart. This study re-evaluates the role of small-conductance Ca-activated K (SK) channels in ventricular repolarization in terminal human heart failure. Although SK protein is present and pharmacological activation causes only minor AP shortening, apamin does not affect action potentials or membrane currents, even with enhanced intracellular Ca. Partial block alone induces repolarization failure, indicating severely reduced repolarization reserve and negligible compensatory SK current, questioning the therapeutic relevance of SK channels in end-stage heart failure.
Gorgodze N, Matsuura TR, Nisini N
… +8 more, Berretta R, Recchia A, Werlen A, Wang T, Batmanov K, Houser S, Kelly DP, Recchia FA
Am J Physiol Heart Circ Physiol
· 2026 Jun · PMID 42059887
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The failing heart displays marked alterations of energy substrate metabolism, with a reduced oxidation of long-chain fatty acids (FA) associated with increased glucose oxidation. Recent preclinical and human studies have...The failing heart displays marked alterations of energy substrate metabolism, with a reduced oxidation of long-chain fatty acids (FA) associated with increased glucose oxidation. Recent preclinical and human studies have shown that the delivery of ketone bodies as an alternative substrate reduces pathological cardiac remodeling and dysfunction in heart failure. However, chronic administration of ketone bodies is challenging. Therefore, using a clinically relevant canine model of tachypacing-induced dilated cardiomyopathy, we tested the hypothesis that other shorter-chain FA may also be beneficial. Seven dogs received cardiac tachypacing and continuous infusion of sodium octanoate, a medium-chain FA, starting after 2 wk of pacing when cardiac dysfunction was still moderate. Six dogs received cardiac pacing with no octanoate infusion. Octanoate did not significantly alter circulating levels of ketone bodies, whereas it still exerted protection, resulting in a delayed progression of systolic and diastolic cardiac dysfunction and normalized myocardial metabolism. These results identify the delivery of medium-chain FA as a potential actionable therapeutic for heart failure with reduced ejection fraction. Octanoate has translational promise due to proven methods of dietary supplementation with no need for parenteral administration. Provision of the medium-chain fatty acid octanoate prevented or reversed key metrics of cardiac functional and metabolic deterioration in a large animal model of dilated cardiomyopathy. Our results demonstrate the cardiac benefits of supplementing a medium-chain FA independent of ketosis in a translational model of heart failure. These findings encourage mechanistic and next-stage translational studies into metabolic interventions for the treatment of heart failure.
Naz H, Teixeiro E, Manrique-Acevedo C
… +1 more, Lastra G
Am J Physiol Heart Circ Physiol
· 2026 Jun · PMID 42053807
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Hypertension and arterial stiffening are major contributors to cardiovascular disease and are closely linked to vascular inflammation. Activation of the renin-angiotensin-aldosterone system promotes unfavorable immune re...Hypertension and arterial stiffening are major contributors to cardiovascular disease and are closely linked to vascular inflammation. Activation of the renin-angiotensin-aldosterone system promotes unfavorable immune responses that lead to vascular inflammation and remodeling; however, the exact molecular mediators connecting immune activation to arterial stiffening remain poorly understood. Transglutaminase 2 (TG2) is a multifunctional enzyme involved in extracellular matrix remodeling and inflammatory signaling, expressed in both vascular and immune cells. We hypothesized that TG2 in myeloid cells facilitates angiotensin II (Ang II)-induced hypertension and aortic stiffening by driving detrimental immune responses. Female mice with myeloid-specific deletion of TG2 (MyTG2KO) and littermate controls were infused with Ang II for 14 days. Ang II infusion resulted in elevated systolic blood pressure, aortic stiffness, and vascular collagen deposition in control mice, whereas these responses were markedly reduced in MyTG2KO mice. Deleting myeloid TG2 lowered vascular expression of proinflammatory markers and circulating cytokines. Flow cytometry analysis showed that Ang II was associated with disruption of immune balance, characterized by decreased regulatory T cells (Tregs) and increased T-helper 17 (Th17) cells; these changes were attenuated in MyTG2KO mice. Consistent with these results, TG2-deficient macrophages promoted Treg development, suppressed Th17 polarization, and decreased CD8 T cell cytotoxicity in coculture experiments. These findings highlight myeloid TG2 as an important contributor to Ang II-related immune imbalance, vascular inflammation, aortic stiffening, and hypertension. Targeting TG2 in myeloid cells could be a novel strategy to reduce immune-driven vascular remodeling in hypertensive cardiovascular disease. This study identifies transglutaminase 2 in myeloid cells as a key regulator of angiotensin II-induced vascular inflammation, aortic stiffening, and hypertension. Myeloid TG2 deletion restores the Treg-Th17 balance and suppresses Ang II-driven inflammatory signaling, revealing an immune-mediated mechanism linking renin-angiotensin-aldosterone system activation to vascular remodeling.
do Carmo JM, Hall JE, Ladnier E
… +6 more, Dai X, Wang Z, Mouton AJ, Omoto ACM, Jorge L, da Silva AA
Am J Physiol Heart Circ Physiol
· 2026 Jun · PMID 42030244
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Alzheimer disease (AD) is a growing health problem characterized by neurocognitive and cardiovascular dysfunction. Although parental obesity programs adverse cardiometabolic complications, including obesity, hypertension...Alzheimer disease (AD) is a growing health problem characterized by neurocognitive and cardiovascular dysfunction. Although parental obesity programs adverse cardiometabolic complications, including obesity, hypertension, and cardiorenal dysfunction in their offspring, whether parental obesity worsens cardiac, metabolic, and cognitive function in lean offspring that are susceptible to AD (3xTg-AD mice) remains unclear. Male and female offspring from control diet-fed or high-fat diet (HFD)-fed parents were examined at 26-28 wk of age. Cognitive function was assessed by Morris water maze and New Object Recognition (NOR) tests, cardiac function by echocardiography and invasive hemodynamic measurements, and mitochondrial (MT) function by high-resolution respirometry in isolated cardiac fibers and brain cortex. AD offspring from obese parents (HFD-Offs) exhibited worse memory retention compared with AD offspring from lean parents [normal diet (ND)-Offs], whereas recognition memory assessed by NOR was not significantly different between groups, although there was greater variability in HFD-Offs. Although systolic function by echocardiography was similar between groups, male HFD-Offs showed impaired diastolic relaxation with prolonged isovolumetric relaxation time, whereas E/e' remained unchanged. Left ventricular catheterization showed reduced indices of contractility and relaxation, including maximal and minimal rates of pressure changes: d/d (8,038 ± 1,011 vs. 18,704 ± 183 mmHg/s), d/d (-7,724 ± 471 vs. -13,634 ± 1,139), and prolonged Tau (4.0 ± 0.1 vs. 2.9 ± 0.1) in HFD-Offs compared with ND-Offs. Male HFD-Offs exhibited reduced MT glucose and fatty acid oxidation in the heart and brain. These findings indicate that parental obesity exacerbates AD-related cognitive decline and cardiac dysfunction in a sex-specific manner, suggesting parental metabolic status as an important determinant of AD-related cardiometabolic vulnerability. Parental obesity is associated with worsened cognitive performance and male-specific impairments in cardiac metabolism and function in AD-susceptible offspring, highlighting developmental programming as a modifier of heart-brain vulnerability.
Am J Physiol Heart Circ Physiol
· 2026 Jun · PMID 42023424
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Although a large percentage of pregnancy-related morbidity and mortality is the result of cardiovascular diseases, little is known about the underlying mechanisms that contribute to the development of adverse cardiac cha...Although a large percentage of pregnancy-related morbidity and mortality is the result of cardiovascular diseases, little is known about the underlying mechanisms that contribute to the development of adverse cardiac changes during pregnancy. It is clear that during pregnancy, the heart adapts to increased ventricular preload through the development of a reversible, pregnancy-induced cardiac hypertrophy. Cardiomyocyte growth must be supported by changes in the cardiac extracellular matrix (ECM), an extremely diverse and dynamic set of components, whose composition and regulation affect cardiac biomechanics. The ECM undergoes extensive remodeling during periods of cardiac stress, such as those experienced during pregnancy and the postpartum period. The full extent of ECM changes and their contributions to biomechanical changes and maternal heart plasticity, however, remain vastly understudied. Recent studies suggest that alterations in the expression of several fibrillar collagens, such as collagens I and III, and regulatory proteins, such as matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases, occur during a healthy pregnancy. On the contrary, in the setting of pregnancy-associated cardiovascular diseases, such as preeclampsia and peripartum cardiomyopathy, adverse changes in ECM remodeling have been reported. This review aims to summarize the current state of the field, highlighting changes in the cardiac ECM and its components during healthy pregnancies, how perturbations in ECM remodeling can lead to the development of pregnancy-related cardiovascular pathologies, and discuss the notable gaps in knowledge that need to be addressed if we are to fully understand ventricular remodeling in the context of pregnancy and reduce maternal cardiovascular disease burden.
Wijesooriya N, Silva S, Kottahachchi D
… +4 more, Badanasinghe N, Chandran DS, Lankadeva YR, Warnakulasuriya T
Am J Physiol Heart Circ Physiol
· 2026 Jun · PMID 42023418
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Type 2 diabetes mellitus (T2DM) is a globally prevalent metabolic disorder frequently complicated by cardiovascular pathologies, notably left ventricular diastolic dysfunction (LVDD), which can progress to heart failure...Type 2 diabetes mellitus (T2DM) is a globally prevalent metabolic disorder frequently complicated by cardiovascular pathologies, notably left ventricular diastolic dysfunction (LVDD), which can progress to heart failure with preserved ejection fraction (HFpEF). There is emerging evidence of a crucial interplay between autonomic dysfunction and chronic low-grade inflammation in the pathogenesis of LVDD in T2DM patients. The bidirectional cross talk between the autonomic nervous system and the immune system has been a novel area explored in preclinical studies. Autonomic dysfunction, as evidenced by reduced heart rate variability and impaired baroreflex sensitivity, is common among patients with T2DM. The interaction between the autonomic nervous system and inflammation is altered in T2DM, shifting toward vagal withdrawal and the release of proinflammatory cytokines [e.g., TNF-α, IL-1β, IL-6, and transforming growth factor-beta (TGF-β)], which can promote myocardial stiffening and fibrosis. These pathophysiological mechanisms, together with metabolic and hemodynamic dysfunction in T2DM, can lead to HFpEF. Neuromodulation techniques, such as vagal nerve stimulation, have shown promise in reducing myocardial fibrosis and HFpEF in preclinical studies. Vagal nerve stimulation is thought to dampen the proinflammatory responses, thereby promoting tissue repair and protecting against cardiac dysfunction. In this review, we explore how inflammation-autonomic cross talk represents a pivotal mechanism in the development of LVDD in T2DM, providing a scientific rationale for neuro-modulatory interventions.
Nakayama Y, Kitaura A, Abdali SA
… +2 more, Nguyen TD, Yoshioka J
Am J Physiol Heart Circ Physiol
· 2026 Jun · PMID 42015926
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Thioredoxin-interacting protein (Txnip), a member of α-arrestin superfamily, is best known for inhibiting thioredoxins and glucose transporters, increasing oxidative and metabolic stress. Through these functions, Txnip h...Thioredoxin-interacting protein (Txnip), a member of α-arrestin superfamily, is best known for inhibiting thioredoxins and glucose transporters, increasing oxidative and metabolic stress. Through these functions, Txnip has emerged as a key contributor to the pathogenesis of heart diseases. Txnip contains C-terminal PPXY motifs that are conserved among α-arrestins across diverse species. Nevertheless, the physiological significance of these motifs remains unknown. We demonstrate that mutation of Txnip PPXY motifs to AAXA uncouples Txnip's canonical functions from its cytotoxic effects. Although the mutant reduced glutathione levels and glucose uptake to the same extent as wild-type Txnip, it attenuated cell death. To assess translational relevance, we engineered inducible, cardiomyocyte-restricted Txnip PPXY-to-AAXA knock-in mice. These mice displayed normal cardiac structure and function at baseline but were strongly protected after myocardial infarction, exhibiting improved left ventricular performance and overall survival. Mechanistically, structural modeling identified the E3 ubiquitin ligase ITCH as the principal PPXY-binding partner. The PPXY mutation abolished Txnip ubiquitination and stabilized Txnip protein, revealing a paradoxical dissociation between Txnip levels and cardiotoxicity. Transcriptomic profiling uncovered enrichment of PPAR-α/PGC-1α-associated pathways, although metabolic assays and untargeted lipidomics did not support these findings. Instead, immediate early genes of the Fos/Jun AP-1 network were consistently downregulated after ischemic injury, and AP-1 DNA-binding activity was diminished in PPXY mutant hearts. These results identify the Txnip PPXY motifs as key regulators of Txnip protein turnover and injury-responsive transcriptional programs. Disruption of these motifs stabilizes Txnip yet confers cardioprotection, providing evidence that elevated Txnip levels do not invariably drive cardiotoxicity. This study reveals that Txnip's conserved PPXY motifs regulate its cytotoxicity independently of its canonical redox and metabolic functions. Mutating motifs (PPXY-to-AAXA) uncouples Txnip function from cell death, stabilizes the protein by preventing Itch-mediated ubiquitination, and confers striking cardioprotection in knock-in mice after myocardial infarction. Despite elevated Txnip levels, mutant hearts show reduced AP-1 signaling and improved survival, demonstrating that PPXY-dependent pathways, not Txnip abundance, drive cardiotoxicity.
Aryal A, Mobasheran P, Bishop L
… +5 more, Chatterjee S, Jennings S, Xia H, Lazartigues E, Yang Q
Am J Physiol Heart Circ Physiol
· 2026 May · PMID 42013057
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Heart failure (HF) affects over 60 million people worldwide, with increasing prevalence as HF with preserved ejection fraction (HFpEF) among adults. Although metabolic remodeling and mitochondrial dysfunction are central...Heart failure (HF) affects over 60 million people worldwide, with increasing prevalence as HF with preserved ejection fraction (HFpEF) among adults. Although metabolic remodeling and mitochondrial dysfunction are central features of HFpEF, the direct mechanistic link between altered cardiac metabolism and mitochondrial impairment remains elusive. Here, we investigated how cardiac metabolic remodeling drives mitochondrial impairment, leading to diastolic dysfunction in HFpEF, independent of extracardiac metabolic syndrome. Infusion of angiotensin II (1.5 μg/g/day) and phenylephrine (50 μg/g/day) in 8- to 10-wk-old male and female mice reproduced hallmark HFpEF features, including preserved EF, elevated E/E' ratio, reduced physical endurance, and impaired lung function. Cardiac mitochondria showed markedly reduced respiration, diminished complex II abundance, and impaired mitochondrial supercomplexes, accompanied by an ∼20% reduction in mitochondrial calcium retention capacity and increased susceptibility to opening of the mitochondrial permeability transition pore (mPTP). Metabolomic analysis suggests a shift in mitochondrial metabolism from fatty acid (FA) to the utilization of alternative glucose substrates, characterized by reduced mitochondrial FA trafficking despite increased FA translocase. Dicarbonyl and glycative stress were substantially elevated, with mitochondrial protein glycation increased by sevenfold. Mass spectrometry identified 18 mitochondrial proteins present in a significantly glycated form, with potential implications for impairing metabolic flexibility, reducing electron transport efficiency, and promoting susceptibility to mPTP opening. Our findings demonstrate that metabolic remodeling contributes to dicarbonyl and glycative stress, which in turn compromises the integrity of mitochondrial electron transport complexes, respiratory function, and calcium retention capacity in the HFpEF heart, highlighting mitochondrial dicarbonyl detoxification and antiglycation strategies as promising therapeutic avenues. Recent studies increasingly highlight profound metabolic remodeling within the HFpEF heart; however, it remains unclear if this is an intrinsic or systemic phenomenon. In the present study, we identify dicarbonyl and glycative stress as key drivers of mitochondrial dysfunction in an ANGII/PE mouse model with HFpEF phenotype independent of systemic metabolic disease. These findings reveal a previously unrecognized metabolic-mitochondrial axis and suggest dicarbonyl detoxification and mitochondrial antiglycation as potential therapeutic targets.
Zehra B, Vinod N, BinEshaq S
… +14 more, Aleksandrova I, Tambi R, Faizan M, Alasrawi S, Almarri M, Brueckner M, Kuebler WM, Chung WK, Almansoori S, Di Donato RM, Uddin M, Du Plessis SS, Alsheikh-Ali A, Berdiev BK
Am J Physiol Heart Circ Physiol
· 2026 Jun · PMID 42013055
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Cardiovascular diseases (CVDs) remain the leading cause of global morbidity and mortality, reflecting a persistent gap between clinical phenotyping and the molecular mechanisms that govern disease initiation, progression...Cardiovascular diseases (CVDs) remain the leading cause of global morbidity and mortality, reflecting a persistent gap between clinical phenotyping and the molecular mechanisms that govern disease initiation, progression, and interindividual variability. Recent advances in emerging technologies have fundamentally reshaped cardiovascular physiology by enabling high-resolution, cross-layer profiling of the heart and vasculature across genomic, epigenomic, transcriptomic, proteomic, metabolomic, lipidomic, glycomic, and fluxomic layers, increasingly at single-cell and spatial resolution. These approaches reveal CVD as a coordinated, multilayered process driven by dynamic interactions among cell types, regulatory programs, and metabolic states, rather than isolated gene-level defects. In this review, we synthesize how emerging multiomic, computational, and functional genomic technologies are redefining the study of cardiovascular disease across molecular, cellular, and tissue levels. We highlight recent innovations in single-cell and spatial atlases, long-read sequencing, proteomics and metabolomics, integrative data modeling, and functional omics approaches, including genome-scale perturbation screens and single-cell perturbation frameworks. These platforms enable mechanistic dissection of regulatory circuits, distinguish primary disease drivers from secondary adaptations, and directly assess therapeutic reversibility, advancing the field beyond associative biomarker discovery toward mechanism-guided target prioritization. We further discuss key methodological and translational challenges accompanying high-dimensional cardiovascular data, including preanalytical variability, control selection, temporal misalignment across molecular layers, population diversity, and reference bias. By integrating technological innovation with computational rigor and functional validation, this review frames emerging omics-enabled strategies as a unified, physiologically grounded framework for translating molecular insight into clinically meaningful cardiovascular phenotypes and advancing precision cardiovascular medicine.
Abdeahad H, Moreno DG, Pontes Oliveira de Almeida AJ
… +3 more, Virgolino da Silva Pontes L, Lesniewski LA, Donato AJ
Am J Physiol Heart Circ Physiol
· 2026 Jun · PMID 42013038
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Endothelial dysfunction is a hallmark of vascular aging and a key contributor to cardiovascular disease. Although senescence has been widely studied as a terminal endothelial cell fate, recent evidence suggests that clon...Endothelial dysfunction is a hallmark of vascular aging and a key contributor to cardiovascular disease. Although senescence has been widely studied as a terminal endothelial cell fate, recent evidence suggests that clonal expansion, the proliferative expansion of genetically identical cells, may also occur in aged tissues. We sought to determine whether endothelial clonal expansion increases with age, specifically at the atheroprone regions of the aorta, and to evaluate whether DNA damage promotes endothelial cell clonal expansion. Tamoxifen-inducible, endothelial-specific Cdh5-CreERT2 male and female mice were used to quantify clonal expansion in endothelial cells (ECs) across the aortic region in both young (4 mo) and aged (24 mo) mice. We further examined the effect of DNA damage by administering systemic doxorubicin (DOXO) to assess clonal dynamics in different aortic regions. Aging significantly increased EC clone size and the percentage of clonal ECs in atheroprone regions, particularly the minor arch, whereas only clone size increased in nonatheroprone regions. Systemic DOXO administration increased clone size across the aortic region without altering clonal recruitment, indicating selective amplification of preexisting clones. These findings suggest that clonal expansion is promoted by both aging and DNA damage. Clonal expansion may represent an underrecognized mechanism contributing to endothelial homogeneity and vascular remodeling during aging and in response to sublethal genomic stress. Aging reshapes the vascular endothelium in unexpected ways. Using lineage tracing in mice, we show that endothelial cells undergo age-dependent clonal expansion, particularly in atheroprone regions exposed to disturbed blood flow. This process is amplified by DNA damage and reflects the selective expansion of preexisting clones rather than increased recruitment. Endothelial clonal expansion may represent an underrecognized mechanism driving vascular remodeling during aging and genotoxic stress.