Comprehensive Physiology最新文献

{"title":"Amyloid-Forming Amylin Secreted by the Pancreas Promotes Hypoxia-Inducible Factor Activation and Mitochondrial Alterations in Liver and Heart During Type 2 Diabetes Pathogenesis.","authors":"Alice E Knapton, Nirmal Verma, Deepak Kotiya, Alice P Sowton, Benjamin D Thackray, Lorenz M W Holzner, Paula M Darwin, Sanda Despa, Florin Despa, Andrew J Murray","doi":"10.1002/cph4.70252","DOIUrl":"10.1002/cph4.70252","url":null,"abstract":"<p><p>In humans, hypersecretion of amyloidogenic amylin (islet amyloid polypeptide, IAPP) in the setting of insulin resistance and type 2 diabetes (T2D) promotes systemic oligomerization and tissue deposition, with deposits identified in failing human hearts and the cerebrovasculature of patients with Alzheimer's Disease. In the renal vasculature, amylin aggregation disrupts microvascular integrity, activating hypoxia signaling pathways and contributing to maladaptive erythropoietic responses, including excess erythrocytosis. We hypothesized that amyloid-forming amylin would activate hypoxia-inducible factor (HIF) signaling, leading to metabolic alterations in liver and heart during T2D pathogenesis. To investigate this, we used the HIP rat, which expresses human amylin specifically in pancreatic β-cells, comparing tissues from 14 to 16-month-old rats with those from age-matched wild-type, hyperglycemic UCD and amylin-knockout (AKO) rats. We found greater accumulation of HIF-1α and HIF-2α in HIP rat livers compared with those in other groups, alongside increased expression of HIF-1 target genes. Mitochondrial ETS capacity was elevated in HIP rat livers, in conjunction with the formation of mitochondrial supercomplexes. Amylin aggregates formed in the hearts of HIP rats, alongside HIF-1α and HIF-2α accumulation. This was associated with suppression of ETS capacity, and increased p-AMPK/AMPK, indicating possible cardiac energetic impairment. Pancreatic secretion of amyloidogenic amylin is thus associated with HIF activation in key metabolic organs beyond the renal vasculature, and occurs alongside mitochondrial alterations in liver and heart that are consistent with sustained hypoxic stress. Our results, alongside previous work, suggest that amylin dysregulation is an overlooked, human-relevant aspect of diabetes pathogenesis, and as such, a potential therapeutic target.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 5","pages":"e70252"},"PeriodicalIF":6.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13545475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148896495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transhepatic Gradients Reveal Selective Hepatic Processing Defects With Systemic Consequences in Cirrhosis.","authors":"Graham Stockdale, Adam Fawaz, Marla Bashour, Kulwant S Aulak, Maria Del Pilar Bayona Molano, Baljendra Kapoor, Raed A Dweik, Adriano R Tonelli","doi":"10.1002/cph4.70255","DOIUrl":"10.1002/cph4.70255","url":null,"abstract":"<p><strong>Background/objectives: </strong>The cirrhotic liver's metabolic capacity remains incompletely characterized, particularly its role in shaping portal metabolite signals that reach the systemic circulation. Transjugular intrahepatic portosystemic shunt (TIPS) placement allows paired portal and right atrial sampling to estimate transhepatic gradients.</p><p><strong>Methods: </strong>We performed global metabolomic profiling on paired portal vein and right atrial samples from 11 patients with cirrhosis during TIPS placement, with right atrial sampling repeated immediately after shunt creation. Pre-TIPS right atrial profiles were compared with peripheral venous samples from 15 healthy controls. For each metabolite, we calculated a transhepatic gradient (portal to pre-TIPS right atrial relative abundance) and a post-TIPS change, and used directional concordance between the two as indirect evidence of hepatic processing. Of 676 metabolites, 612 had sufficient paired data.</p><p><strong>Results: </strong>Of 676 metabolites, 305 (45.1%) differed between cirrhotic patients and controls at <i>q</i> < 0.1, with 170 elevated and 135 depleted. Among 612 metabolites with paired data, 124 changed after TIPS at <i>p</i> < 0.05, and 113 (91.1%) were directionally concordant with their pre-TIPS transhepatic gradients. Fifty of these showed impaired hepatic extraction and 63 showed a hepatic dilution pattern.</p><p><strong>Conclusions: </strong>The cirrhotic liver retains measurable but selective metabolite processing, with disruption that may carry consequences beyond the liver itself. Cirrhosis is better understood as a disorder of hepatic signaling with systemic consequences than as uniform hepatic failure.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 5","pages":"e70255"},"PeriodicalIF":6.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13569944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Axial Connectivity of the Lung Microbiome: A Review of Interorgan Crosstalk.","authors":"Mathangi Palanivel, Jayanth Kumar Narayana, Sanjay H Chotirmall","doi":"10.1002/cph4.70269","DOIUrl":"10.1002/cph4.70269","url":null,"abstract":"<p><p>The classic organ-centric model of human physiology is rapidly giving way to a unified approach embracing the human body as an integrated network of bidirectional interorgan communication. The human microbiome serves as a fundamental mediator of this shift, regulating immune homeostasis, barrier integrity and metabolic signaling across organs. While the lung maintains a characteristic low-biomass microbiome in dynamic equilibrium, any disruption primes local and systemic immune responses contributing to disease. Beyond the well-described gut-lung axis, crosstalk between the lung and other distal organ systems is lesser recognized; however, increasingly acknowledged as a key under-appreciated contributor to respiratory disease including extrapulmonary complications. This review synthesizes current established evidence on axial connectivity of the lung microbiome across the gut, brain, skin, heart, kidney, and liver, and finds that such crosstalk is predominantly, though not exclusively gut-mediated. Direct lung-organ interactions are described for several axes; however, they remain preliminary. Across these lung-axial systems, common pathophysiological mechanisms emerge, including dysbiosis-induced depletion of microbial metabolites, immunomodulation, and barrier perturbations, all linking pulmonary disease with neuroinflammation, gastrointestinal deficits, and cardiac, renal, hepatic, and dermatological abnormalities. We assess how therapeutic modulation of interorgan systems offers promising avenues for improved risk stratification and novel therapeutics. Recognizing microbiome-mediated pulmonary-organ crosstalk represents an emerging conceptual framework in respiratory medicine, repositioning microbial communities as key modulators of extrapulmonary disease.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 5","pages":"e70269"},"PeriodicalIF":6.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589154/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149008010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ghrelin Drives Food Intake by Attentional Bias Toward Food Cues.","authors":"Renée Poelman, Marie V Le May, Iris Stoltenborg, Edoardo Vecchi, Erik Schéle, Roger A H Adan, Suzanne L Dickson","doi":"10.1002/cph4.70281","DOIUrl":"https://doi.org/10.1002/cph4.70281","url":null,"abstract":"<p><p>Food-predictive cues can promote eating, but the contribution of metabolic signals to cue-guided behavior remains incompletely understood. Ghrelin is an orexigenic hunger hormone that has previously been linked to behavioral and neural responses to food-predictive cues, although many paradigms cannot distinguish general hunger-driven intake from intake expressed in response to discrete conditioned cues. We developed a home-cage operant task using the Feeding Experimentation Device 3 (FED3) to assess attention-linked responding to an illuminated food-predictive food cue in male mice. Following staged training, eight mice were tested under fed, overnight-fasted and ghrelin-treated conditions in a crossover design. Fasting and ghrelin increased correct and premature responses, and reduced omissions, indicating enhanced engagement with the conditioned food cue, with motivational and impulsivity-related processes likely contributing to the behavioral profile. Ghrelin increased food intake during the cue-guided task but not during FreeFeeding in the absence of the illuminated predictive cue, whereas fasting increased intake in both contexts. The maximum obtainable food intake was elevated by fasting and ghrelin, but only during the cue-guided task. These findings establish a home-cage FED3-based paradigm for resolving multiple attention-linked components of food-cue responding and show that acute ghrelin and fasting produce overlapping effects on cue-guided engagement but differ in their effects on food intake across task contexts, with ghrelin preferentially increasing intake when food availability is signaled by a conditioned cue.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 5","pages":"e70281"},"PeriodicalIF":6.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond the Heart-Lung Axis: A Review of the Crosstalk Between the Hemodynamic, Neurohormonal, and Immune Systems in Pulmonary Hypertension.","authors":"Alejandro A Vega, Juliet M Alfaro, David S Pinto, Maryam Emamimeybodi, Soban Umar","doi":"10.1002/cph4.70266","DOIUrl":"10.1002/cph4.70266","url":null,"abstract":"<p><p>Investigating systemic interactions involving interorgan crosstalk in pulmonary arterial hypertension (PAH) may elucidate the underlying mechanisms that drive pathogenic processes. Further understanding of the disease process through communication pathways at the broader physiological level can inform advancements in novel therapeutic approaches. This article is a comprehensive summary of our current knowledge surrounding the heart-lung axis in PAH as well as systemic pathophysiological contributions and their methods of communication through neurohormonal, inflammatory, metabolic, and extracellular mediated pathways. Neurohormonal crosstalk encompasses the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS), both of which modulate communication between the heart and lung. Inflammation, within the heart-lung axis and at the systemic level, is characterized by cytokine signaling and chemokine recruitment. Extrapulmonary mediators of inflammation in PAH include the liver, chronic kidney disease (CKD), adipose tissue, insulin resistance, and bone marrow-derived cells. Extracellular vesicles mediate proximal to distal communication pathways, spanning from localized crosstalk between the heart and lungs to peripheral interorgan signaling. Emerging studies have revealed broader physiological contributions across multiple organ systems in PAH pathogenesis, such as pulmonary vascular remodeling and endothelial cell dysfunction, suggesting systemic interorgan crosstalk with the heart and lungs influences the disease phenotype.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 5","pages":"e70266"},"PeriodicalIF":6.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13598275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatic HIF2α Modulates Extra-Hepatic Disease-Associated Phenotypes During Metabolic Dysfunction-Associated Steatotic Liver Disease.","authors":"Lorenz M W Holzner, Rosa M Korpershoek, Youguo Niu, Anna Cochrane, Paula M Darwin, Julia Babuta, Areesha Nazeer, Cecilia Castro, Alice P Sowton, Alice E Knapton, Benjamin D Thackray, Julian L Griffin, Zoe Hall, Dino A Giussani, Rob C I Wüst, Andrew J Murray","doi":"10.1002/cph4.70283","DOIUrl":"https://doi.org/10.1002/cph4.70283","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) afflicts more than one-third of adults globally, contributing significantly to an increased cardiovascular disease risk. Further, patients with severe liver disease experience muscle weakness and fatigue. Hypoxia-inducible factor 2α (HIF2α) accumulates in the livers of MASLD patients. Here we sought to understand the role of hepatic HIF2α in mediating hepatic and extra-hepatic features of MASLD. Using an obese mouse model of MASLD, we investigated the impact of hepatocyte-specific HIF2α deletion (hHIF2α^-/-) on hepatic, cardiac and skeletal muscle metabolism, and cardiac function. Over 28 weeks, mice were exposed to a high-fat, high-fructose, high-cholesterol (GAN) diet, which induced obesity, hepatic steatosis, fibrosis and inflammation. hHIF2α^-/- was associated with greater hepatic NADH-supported mitochondrial respiration, higher sphingomyelin levels and protection against MASLD induced hyperinsulinaemia, but not against hepatic manifestations of MASLD. Instead, in the hearts of GAN-fed mice, hHIF2α^-/- caused diacylglycerol and long-chain acyl-carnitine accumulation and exacerbated diet-induced ceramide accumulation. Langendorff-perfused hearts from hHIF2α^-/- mice showed systolic and diastolic dysfunction, including 24% lower left ventricular developed pressure and 34% lower maximal rate of relaxation (dP/dt_min). However, isolated hearts from hHIF2α^-/- mice were protected against MASLD-associated sympathetic dominance, determined using autonomic receptor agonist stimulation. Both GAN-feeding and hHIF2α^-/- were associated with lower lean mass (14% and 5.4% lower than respective controls), whilst hHIF2α^-/- enhanced OXPHOS-associated protein levels in gastrocnemius muscle. Overall, hHIF2α^-/- resulted in detrimental extra-hepatic effects, including myocardial lipid accumulation, impaired cardiac function, and loss of whole-body lean mass, thereby worsening the systemic presentation of MASLD-associated pathological features.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 5","pages":"e70283"},"PeriodicalIF":6.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13652961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Short-Chain Fatty Acids: Microbial Metabolites Driving Gut-Eye Axis Signaling.","authors":"Aleah J Brokemond, Ronny Amamoo, Fapianey J Alexandre, Sewedo B Ajisegiri, Menaka C Thounaojam, Pamela M Martin, Ravirajsinh N Jadeja","doi":"10.1002/cph4.70251","DOIUrl":"10.1002/cph4.70251","url":null,"abstract":"<p><p>Short-chain fatty acids (SCFAs) have emerged as key molecular mediators of gut-eye communication, linking microbial metabolism to ocular physiology and disease. Produced through microbial fermentation of dietary fiber, SCFAs function as systemic signaling molecules that regulate immune homeostasis, metabolic function, vascular integrity, and neuroinflammatory pathways through activation of SCFA-responsive receptors and epigenetic mechanisms. Growing evidence indicates that SCFAs influence biological processes central to ocular health, including inflammation, oxidative stress, neurodegeneration, and pathological angiogenesis. Experimental, metabolomic, and emerging clinical studies suggest that disruptions in SCFA signaling may contribute to the pathogenesis of retinal and ocular surface diseases; however, the mechanisms governing ocular exposure, target engagement, and therapeutic efficacy remain incompletely understood, highlighting a critical gap between mechanistic insight and clinical translation. In this review, we integrate current evidence into a mechanistic and translational framework that positions SCFAs as central effectors of the gut-eye axis. We further evaluate the therapeutic potential of SCFA modulation and identify key barriers to clinical implementation, including bioavailability, pharmacokinetics, dosing, and long-term safety, thereby delineating a roadmap for the development of microbiome-derived precision therapeutics in ophthalmology.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 5","pages":"e70251"},"PeriodicalIF":6.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13559049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lung-Cardiovascular Interactions and Derangements in ARDS.","authors":"Pablo A Sanchez, Connor O'Brien, Matthieu Legrand, Carolyn S Calfee, Michael A Matthay","doi":"10.1002/cph4.70254","DOIUrl":"10.1002/cph4.70254","url":null,"abstract":"<p><p>The acute respiratory distress syndrome (ARDS) is fundamentally characterized by alveolar injury, leading to lung edema, severe hypoxemia, and poorly compliant lungs. Alveolar and cardiovascular pathology are deeply intertwined in the syndrome, which can be marked by clinical cardiac, pulmonary, and systemic vascular abnormalities. Pulmonary vascular dysfunction is common even in the era of lung-protective ventilation, is associated with right ventricular (RV) dysfunction, and worse mortality. Frustratingly, these cardiovascular abnormalities pose management challenges for which we have limited targeted therapies that improve clinical outcomes. Recent inroads disentangling patient heterogeneity in ARDS may offer a direct avenue connecting biological mechanisms to effective treatments. Throughout this review, we will examine the clinical involvement of the cardiovascular system in ARDS, grounded on pathological and biological studies, and review available evidence for potential targeted therapies.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 5","pages":"e70254"},"PeriodicalIF":6.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13554470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148918841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lung Pericytes: Molecular Mechanisms, Signaling Pathways, and Roles in Pulmonary Diseases.","authors":"Stuti Agarwal, Anuradha Bankar, Vinicio A de Jesus Perez","doi":"10.1002/cph4.70205","DOIUrl":"10.1002/cph4.70205","url":null,"abstract":"<p><p>Pericytes are specialized mural cells that ensheathe microvessels and play critical roles in maintaining vascular homeostasis, regulating angiogenesis, and coordinating tissue repair. Studies in the systemic circulation have established that pericytes contribute to the pathogenesis of major vascular diseases, including stroke, myocardial infarction, and retinopathy, increasing interest in understanding their roles in both health and disease. In contrast, our understanding of pericyte biology in the lung remains relatively limited. Over the past 15 years, a growing body of evidence emphasizes that lung pericytes actively participate in vascular remodeling and inflammatory responses, pointing to an important role for these cells in the pathogenesis of multiple pulmonary diseases. This comprehensive review synthesizes current knowledge on the molecular mechanisms governing lung pericyte function, with particular emphasis on key signaling pathways including PDGF-BB/PDGFRβ, TGFβ/ALK1/ALK5, VEGF/VEGFR, Angiopoietin/Tie2, Notch, Wnt, and sphingosine-1-phosphate (S1P). We examine how these pathways orchestrate pericyte recruitment, proliferation, differentiation, and phenotypic transitions through complex downstream signaling cascades involving kinases, transcription factors, and mechanotransduction mechanisms. The review further explores the multifaceted roles of pericytes in major pulmonary diseases, including acute lung injury and acute respiratory distress syndrome (ALI/ARDS), pulmonary fibrosis, pulmonary arterial hypertension (PAH), lung cancer, and lung infections.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 4","pages":"e70205"},"PeriodicalIF":6.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13320175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting mTOR to Mitigate Sequelae of Chronic Hypoxia on the Carotid Artery and Cerebral Circulation.","authors":"Rira Choi, Jelena Mihailovic, Prapti Sharma, Fadi Nikola, Sydney L Bluestein, Pramath Doddaballapur, Nicole Guerrera, Nebal S Abu Hussein, Cristina Cavinato, Taylor S Adams, Xiting Yan, Fahmeed Hyder, Peter Herman, Jay D Humphrey, Edward P Manning","doi":"10.1002/cph4.70240","DOIUrl":"https://doi.org/10.1002/cph4.70240","url":null,"abstract":"<p><p>We hypothesized that vascular maladaptations resulting from chronic hypoxemia worsen end-organ function via insidious positive feedback. To test this hypothesis in the systemic circulation, we quantified brain perfusion and left heart function and then biomechanically phenotyped the left common carotid artery (LCCA) in adult female mice under normoxic (21% oxygen) and chronic hypoxic (10%) conditions. Functional MRI revealed that hypoxia impaired cerebrovascular reactivity during transient hypercapnia (pCO₂ 5%) while echocardiography revealed altered left ventricular diastolic, but not systolic, function. These end organ changes associated with an 18.8% decrease in distensibility of the LCCA due to a 34.4% increase in circumferential material stiffness without an increase in wall thickness. This finding suggested a change in the state (e.g., collagen microstructure), not amount, of the LCCA extracellular matrix. Active biaxial testing of the LCCA further revealed up to an 11% reduction of SMC contractility in response to vasoactive agents. Treatment with the mTOR inhibitor rapamycin improved LCCA properties in hypoxic mice, as reflected by a 53.37% increase in distensibility and a 43% improvement in contractility relative to the hypoxic group. We conclude that chronic hypoxia causes multiorgan effects: stiffer carotid arteries having impaired vascular reactivity associate with impaired cerebral and cardiac function. Maladaptive LCCA changes are prevented with mTOR inhibition during hypoxia, suggesting mTOR as a potential target to break the insidious feedback loop that leads to hypoxia-induced maladaptive remodeling and to mitigate associated end-organ dysfunction, with possible advantages to single ventricle patients who experience long periods of hypoxemia.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 4","pages":"e70240"},"PeriodicalIF":6.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13478350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148789138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}