Comprehensive Physiology最新文献

{"title":"Heart-Specific Spinal and Vagal Afferents: Transcriptomic Signatures and Optogenetically Modulated Functional Coupling With Cardiomyocytes.","authors":"T Akgul Caglar, Y E Kazci, Z B Durdu, S Sahoglu Goktas, S Bay, E Vatandaslar, M U Turhan, G Ozturk, E Cagavi","doi":"10.1002/cph4.70203","DOIUrl":"10.1002/cph4.70203","url":null,"abstract":"<p><p>Sensory neurons innervating the heart transmit chemical and mechanical cues to the central nervous system via the dorsal root ganglion (DRG) and nodose ganglion (NG). Despite their importance in cardiac pain and cardiovascular reflexes, the molecular and functional properties of heart-specific sensory (HS) neurons remain elusive. Here, DRG^HS and NG^HS neurons innervating the heart were FACS purified using a retrograde labeling strategy with Di-8-ANEPPQ, then characterized molecularly by bulk RNA sequencing or evaluated functionally in cocultures with neonatal cardiomyocytes. DRG^HS and NG^HS neurons formed functional connections with neonatal cardiomyocytes as demonstrated by immunolabeling, electron microscopy, and optogenetic manipulation. Functionally coupled DRG^HS neurons exhibited enhanced spontaneous and evoked Ca²⁺ activity in response to optogenetic and chemical stimulation, indicating dynamic neuro-cardiac communication. Global RNA sequencing analysis revealed that DRG^HS and NG^HS neurons exhibited distinct transcriptomic profiles, including enrichment of transcripts encoding ion channels and G protein-coupled receptors, compared with their respective total populations. In DRG^HS tissue, these included Scn10a, P2xr2, and Mrgprd, whereas NG^HS neurons preferentially expressed P2xr2, Ptgdr, and Cckar, collectively supporting a combination of molecular signatures including nociceptors. Collectively, these findings define molecularly distinct sensory pathways connecting the heart and the sensory nervous system, providing mechanistic insights and highlighting potential targets for modulation of cardiovascular reflexes and hemostasis.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 4","pages":"e70203"},"PeriodicalIF":6.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13320145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359444","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":"Cytokine Gene Variants Are Associated With Aerobic Fitness-Related, Hematological, and Metabolic Traits in Healthy Adults.","authors":"Kinga Humińska-Lisowska, Barkın Bıçakçı, Monika Michałowska-Sawczyn, Piotr Aschenbrenner, Alison V September, Patrizia Proia, Agata Leońska-Duniec","doi":"10.1002/cph4.70234","DOIUrl":"10.1002/cph4.70234","url":null,"abstract":"<p><p>Genetic variation in cytokine genes may influence cytokine-related signaling, metabolism, and exercise-related phenotypes, yet large-scale population data remain scarce. This study examined whether five polymorphisms in interleukin-6 (IL6; rs1800795; rs1800796; rs1800797), interleukin-15 (IL15; rs1589241), and tumor necrosis factor-alpha (TNF-α; rs1800629) associate with physiological, biochemical, and performance-related traits in healthy adults. For VO₂max-stratified analyses, 501 healthy Polish adults underwent physiological, biochemical, and genomic assessments, classified by maximal oxygen uptake using sex-and age-adjusted reference categories. Whole-cohort analyses were performed for biochemical and hematological traits in up to 962 participants. IL6 rs1800795 CC genotype showed an exploratory higher serum-iron (<i>p</i> = 0.004) and hematocrit (<i>p</i> = 0.033). The <i>IL6</i> C-G-G haplotype (rs1800795-rs1800796-rs1800797) was associated with higher serum-iron (<i>p</i> = 0.0012, within-phenotype FDR-adjusted <i>p</i> = 0.002). <i>TNF-α</i> rs1800629, showed a model-dependent association with lower aerobic fitness classification in grouped analyses (<i>p</i> = 0.006). A-allele carriers had lower odds of higher-fitness classification under the dominant model and AG heterozygotes showed the strongest association under overdominant model. Grouped analyses; AG heterozygotes (<i>p</i> = 0.037) had higher LDL cholesterol, was not retained in whole-cohort adjusted-analyses. <i>IL15</i> showed no single-locus effects but an exploratory multi-locus genotype combination, <i>IL15</i> CC/CT × <i>TNF-α</i> GG, associated with higher odds of aerobic fitness classification (<i>p</i> = 0.004). Whole-cohort analyses: <i>IL6</i> rs1800795 was associated with serum-iron, hematocrit, hemoglobin, and RBC after adjustments. Findings provide preliminary evidence of modest, trait-specific associations between cytokine-related genetic variation and hematological, metabolic, and aerobic fitness-related phenotypes. <i>IL6</i> rs1800795 mainly associated with iron-related and hematological traits; <i>TNF-α</i> rs1800629 findings were model-dependent and inconsistent. <i>IL15</i> CC/CT × <i>TNF-α</i> GG combination is exploratory, requiring independent replication.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 4","pages":"e70234"},"PeriodicalIF":6.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13428184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148663604","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":"Determinants of Abnormal Pulmonary Vasodilatory Response With Exercise in HFpEF: Pulmonary Vascular-Left Atrial Axis Abnormalities.","authors":"Mariana Garcia-Arango, Angela Kristo, Ahmed El Shaer, Yimin Chen, Aditya Sahai, Anas Abed, Wanxin Tu, Soham Ghosh, Babak Tehrani, Shannon Heffernan, Amir Esmaeeli, Tashfeen Javaid, Ran Tao, Naga Dharmavaram, James Runo, Alejandro Roldán-Alzate, Adam D Gepner, Matthew Kalscheur, Colleen M Witzenburg, Ryan J Tedford, Farhan Raza","doi":"10.1002/cph4.70229","DOIUrl":"10.1002/cph4.70229","url":null,"abstract":"<p><strong>Background: </strong>Inability to decrease pulmonary vascular resistance (PVR) with exercise may lead to right ventricular failure. In this two-step study, we define an unfavorable exercise PVR response among a broad cohort and then determine its high-risk correlates in HFpEF.</p><p><strong>Methods: </strong>164 participants (80 HFpEF, 57 pre-capillary PH, 27 non-cardiac dyspnea) underwent invasive cardiopulmonary exercise test. Dichotomous groups were created with a stepwise approach: \"unfavorable exercise PVR\" (<i>n</i> = 85, HFpEF = 46) defined as exercise PVR > 1.74Woods unit (WU) and ∆PVR decrease with exercise of < 22%, the remainder of the cohort was labeled as \"favorable exercise PVR\" (<i>n</i> = 79, HFpEF = 34). Stepwise approach included: physiological groups (tertiles) using exercise PVR cutoff = 1.74 WU and median approach with ∆PVR decrease with exercise.</p><p><strong>Results: </strong>In unfavorable (vs. favorable) PVR HFpEF subgroups, rest PVR = 3.4 ± 2.0 vs. 2.9 ± 2.0WU, exercise PVR = 3.7 ± 2.6 vs. 2.0 ± 1.3WU, and ∆PVR = +11% ± 39% vs. -26% ± 22%. Correlates of unfavorable exercise PVR with univariate regression were: atrial fibrillation, COPD, increased LAVI, lower TAPSE, and lower TAPSE/PASP. Multivariate model (including clinical data: age, sex, BMI) revealed that atrial fibrillation (β-estimate = 1.93, <i>p</i> = 0.003) and COPD (β-estimate = 1.74, <i>p</i> = 0.03) were significant. However, with multivariate model (including LAVI and TAPSE), COPD remained significant (β-estimate = 3.26, <i>p</i> = 0.02), while atrial fibrillation (β-estimate = 1.60, <i>p</i> = 0.06) and LAVI (β-estimate = 0.05, <i>p</i> = 0.09) approached significance. The unfavorable versus favorable exercise PVR HFpEF subgroups had similar biventricular morphology by cardiac MRI (<i>p</i> < 0.30).</p><p><strong>Conclusions: </strong>Compared to traditional cardiometabolic comorbidities, COPD and atrial fibrillation are uniquely linked to pulmonary vascular remodeling in HFpEF. The impact of these two comorbidities on pulmonary vascular-left atrial axis is highlighted by the shared biventricular morphology among HFpEF subgroups.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 4","pages":"e70229"},"PeriodicalIF":6.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13402025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148590720","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":"The Interstitial Fluid Compartment: Still Unrecognized or Biophysically Well Described?","authors":"Daniela Negrini, Giuseppe Miserocchi","doi":"10.1002/cph4.70213","DOIUrl":"10.1002/cph4.70213","url":null,"abstract":"<p><p>The proposal of a \"new third bodily system for circulation of fluid\" has been recently put forward. The present article sheds light on all available physiological knowledge concerning exactly this same space, defined as \"interstitial compartment\" as originally hypothesized by Ernest Starling about 130 years ago. We provide here a brief updated summary of the main morpho-functional features and corresponding analysis concerning capillaries microfiltration, interstitial fluid dynamics, and lymphatic drainage.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 4","pages":"e70213"},"PeriodicalIF":6.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13342484/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403894","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":"The Immuno-Cardiovascular Storm of Pre-Eclampsia: Cytokine-Mediated Endothelial Injury, Thrombosis, and Maternal Cardiovascular Instability.","authors":"Emmanuel Ifeanyi Obeagu","doi":"10.1002/cph4.70209","DOIUrl":"10.1002/cph4.70209","url":null,"abstract":"<p><p>Pre-eclampsia is a complex multisystem hypertensive disorder of pregnancy and a leading cause of maternal and perinatal morbidity and mortality worldwide. Increasing evidence suggests that the condition extends beyond abnormal placentation and represents an integrated immuno-cardiovascular disorder characterized by immune dysregulation, endothelial dysfunction, thromboinflammation, and cardiovascular maladaptation. This narrative review examines the interconnected mechanisms linking cytokine-mediated inflammation, endothelial injury, coagulation abnormalities, and maternal cardiovascular instability in pre-eclampsia. A structured literature search of major biomedical databases was conducted to identify relevant experimental, clinical, and translational studies addressing inflammatory cytokines, angiogenic imbalance, endothelial dysfunction, thrombosis, biomarkers, and therapeutic strategies in pre-eclampsia. The review highlights the central roles of pro-inflammatory mediators, including tumor necrosis factor-α, interleukin-6, interleukin-17, and interferon-γ, in promoting oxidative stress, vascular inflammation, and endothelial dysfunction. Particular attention is given to the development of an immunothrombotic environment, defined as the pathological interaction between immune activation and coagulation pathways that promotes thrombosis and vascular injury. The review also critically evaluates the contribution of antiangiogenic factors, platelet activation, impaired fibrinolysis, and cardiovascular remodeling to maternal disease progression. In addition, current and emerging therapeutic approaches targeting inflammatory, endothelial, angiogenic, and thrombotic pathways are discussed, together with their translational potential and clinical limitations. By integrating immunological, vascular, hematological, and cardiovascular perspectives, this review provides a comprehensive framework for understanding the pathophysiology of pre-eclampsia and identifies important knowledge gaps for future investigation.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 4","pages":"e70209"},"PeriodicalIF":6.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13320153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359476","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":"The Temporal Effects of Hyperbaric Oxygen Intervention on Heart Rate Variability in Young Adults.","authors":"Hongyang Zhang, Hao Liu, Zhu Huang, Yan Fu, Yanli Liu, Dan Wu, Xiaoping Dan, Juan Gao, Haixia Yang, Haifeng Pei","doi":"10.1002/cph4.70169","DOIUrl":"10.1002/cph4.70169","url":null,"abstract":"<p><strong>Objective: </strong>This prospective cohort study aimed to investigate the temporal effects and additional characteristics of hyperbaric oxygen (HBO) intervention on heart rate variability (HRV) and autonomic nervous system (ANS) function in young adults.</p><p><strong>Methods: </strong>Portable single-lead ambulatory ECG devices were used to collect HRV data. Fourteen young male participants underwent five daily 90-min HBO sessions. HRV was measured before intervention (T0), 2 h after the fifth session (T1), and 1 month later (T2). Circadian variation characteristics were further investigated by segmenting data into daytime and nighttime periods and calculating ΔHRV.</p><p><strong>Results: </strong>Following five HBO sessions, the young adults showed progressive increases in HTI, TINN, and DFAα2 from T0 to T2, with TINN significantly higher at T2 than at T0 (p < 0.05). Sympathetic tone-related indices (daytime SDANN, SDNNI, and SD2) were significantly higher at T2 compared to T0 (p < 0.05), and their corresponding ΔHRV values were significantly reduced at T2 (p < 0.05). However, no significant changes were observed in vagal tone indicators (such as RMSSD, NN50, HF, SD1) or other HRV parameters. The maximal heart rate at T2 was significantly lower than at T0 (p = 0.036).</p><p><strong>Conclusion: </strong>Five sessions of HBO intervention significantly enhanced the overall ANS function in young adults during the daytime 1 month post-intervention, reduced heart rate and daytime sympathetic activity, and effectively narrowed circadian differences in both overall ANS and sympathetic function. No significant effects were observed on vagal tone related indices.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70169"},"PeriodicalIF":6.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiopulmonary Interactions in Combined Septic Shock and ARDS: An Integrative Framework for Phenotyping and Hemodynamic Optimization.","authors":"Athanasios Chalkias","doi":"10.1002/cph4.70176","DOIUrl":"10.1002/cph4.70176","url":null,"abstract":"<p><p>The syndromic convergence of septic shock and acute respiratory distress syndrome represents a critical nexus of pathophysiological complexity, marked by profoundly elevated mortality and governed by multifaceted, temporally dynamic cardiorespiratory interactions. Conventional hemodynamic management paradigms frequently fail to achieve optimal outcomes, owing to their insufficient accommodation of the bidirectional and nonlinear interdependence between respiratory system derangements and cardiovascular stress responses. This review systematically re-examines the underlying mechanistic architecture of these interactions, commencing with a reappraisal of the canonical Guyton model of circulatory equilibrium, followed by an in-depth delineation of the respiratory cycle's modulatory influence on cardiac preload, afterload, and ventricular interdependence. Central to the analysis is the contention that acute respiratory distress syndrome should be mechanistically phenotyped into \"pulmonary\" and \"extra-pulmonary\" subtypes, a nosological distinction with direct implications for divergent hemodynamic trajectories under mechanical ventilation. Emerging integrative models-synthesizing respiratory mechanics with advanced circulatory physiology-are presented to conceptualize and visualize these complex feedback loops. This framework converges upon the pivotal determinant of hemodynamic stability: the coupling ratio between right ventricular contractile performance, quantified by end-systolic elastance, and the imposed pulmonary arterial load, represented by effective arterial elastance. The overarching aim is to advance an integrative, mechanistically anchored, and clinically actionable schema capable of enhancing diagnostic granularity, guiding individualized hemodynamic optimization, and ultimately improving survival in this uniquely unstable and high-acuity patient cohort.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70176"},"PeriodicalIF":6.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147986881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KCNK16 Deficiency Deteriorates Body Growth and Diet-Independently Decreases Lipid Accumulation in Mice.","authors":"Olena Früh, Jennifer Winkler, Jana M Jäger, Rongwan Sun, Aoxue Liu, Niklas Hegemann, Jana Grune, Atsuyo Ikeda, Andreas Diefenbach, Matthias Schäfer, Uwe Schwahn, Johann Gassenhuber, Klaus Steinmeyer, Joachim Spranger, Knut Mai, Sebastian Brachs","doi":"10.1002/cph4.70180","DOIUrl":"10.1002/cph4.70180","url":null,"abstract":"<p><strong>Background: </strong>The potassium channel KCNK16 (TALK-1) is highly expressed in murine and human pancreas and has been implicated in regulating β-cell electrical excitability and glucose-stimulated insulin secretion (GSIS). Genetic studies have linked KCNK16 variants to type 2 diabetes (T2D), yet its physiological role in vivo remains largely unexplored. We aimed to characterize the cardiometabolic functions of KCNK16 in mice.</p><p><strong>Methods: </strong>Male constitutive Kcnk16-deficient mice (KCNK16^-/-) were characterized on standard (STD) or high-fat diet (HFD) for up to 21 weeks. Phenotyping included measurements of body weight and composition, echocardiography, blood pressure, and indirect calorimetry. Insulin and glucose homeostasis were assessed by tolerance tests and glucose clamp studies.</p><p><strong>Results: </strong>KCNK16^-/- mice showed lower weight gain, less fat and lean mass, reduced diet intake, and shorter body length across diets. Glucose tolerance, insulin sensitivity, hepatic lipid content, and cardiac function remained largely unaffected, except for lower systolic blood pressure under STD. During HFD, KCNK16^-/- mice exhibited increased energy expenditure but attenuated first-phase insulin secretion. Pancreatic insulin content was elevated while circulating IGF-1 was diminished.</p><p><strong>Conclusion: </strong>Kcnk16 deficiency reduced somatic growth and body weight and altered energy expenditure, accompanied by modest changes in insulin secretion dynamics, while glucose homeostasis remained preserved.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70180"},"PeriodicalIF":6.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148053166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sexual Dimorphism in Metabolic Dysfunction-Associated Steatotic Liver Disease: The Emerging Role of Non-Coding RNAs.","authors":"Yang En-Xi Chen, Amir Amir Samih Sadek, Fang Li, Guo-Zheng Zhang, Ning-Lin Wu, Xiao-Dong Sun, Mohamed El-Kassas, Ahmed Ihab Abdelaziz, Yuan-Yuan Zhang, Injie Omar Fawzy","doi":"10.1002/cph4.70156","DOIUrl":"10.1002/cph4.70156","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) exhibits marked sexual dimorphism, with lower prevalence and slower progression in premenopausal women versus men and postmenopausal women. While sex hormones, sex chromosome complement, and metabolic differences are contributors, molecular mediators linking biological sex to divergent MASLD trajectories remain incompletely defined. Evidence implicates non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, and circular RNAs, as critical regulators of gene expression networks implicated in hepatic lipid metabolism, insulin resistance, inflammation, and fibrogenesis in a sex-dependent manner. This review synthesizes epidemiological, experimental, and mechanistic data demonstrating sex-biased hepatic ncRNA expression and its integration with sex hormone signaling, X-chromosome biology, and epigenetic regulation. We propose a hierarchical mechanistic framework in which sex hormones act as upstream regulators that shape hepatic transcriptional and epigenetic landscapes, while ncRNAs function as context-dependent integrative nodes that propagate these signals across cell types, including hepatocytes, Kupffer cells, and hepatic stellate cells. Through this lens, ncRNAs are positioned as key mediators linking hormonal signaling to downstream pathogenic pathways in MASLD. We highlight evidence for ncRNAs as potential sex-specific biomarkers and therapeutic targets, and discuss challenges facing ncRNA-based interventions. We evaluate the current evidence base, noting the predominance of preclinical studies and limited availability of human datasets. Finally, we discuss emerging technologies, including single-cell, spatial, and integrative multi-omics approaches, poised to refine our understanding of sex-specific regulatory networks in MASLD, and emphasize the need for sex-stratified studies to elucidate ncRNA-mediated mechanisms underlying MASLD sexual dimorphism and enable precision medicine strategies tailored to biological sex.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70156"},"PeriodicalIF":6.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vascularization Is Driven by Sprouting and Subsequent Splitting: Mechanisms of Physiological Angiogenesis in a Porous Biomaterial Scaffold and Intervention Insights.","authors":"Kuihua Zhan, Lun Bai","doi":"10.1002/cph4.70170","DOIUrl":"10.1002/cph4.70170","url":null,"abstract":"<p><p>Vascularization is a prerequisite for the in vivo survival of tissue engineering constructs, especially large-scale ones. However, due to inadequate research on the underlying mechanisms of physiological angiogenesis in biomaterials, the ability of emerging biotechnologies to facilitate the clinical translation of regenerative medicine strategies is compromised. In contrast, systematic research on these relevant mechanisms can provide key theoretical insights for the development of novel engineering strategies. Taking subcutaneous implantation of a thin, unloaded porous scaffold as the experimental model, this study investigates the progression of its spontaneous physiological vascularization. The experimental results reveal that vascularization is driven by sprouting angiogenesis and subsequent splitting angiogenesis. Specifically, the scaffold is neovascularized by sprouting which is induced by pro-angiogenic factors in the avascular area. This is a spatial process in which a primary vascular network forms and expands from the superficial to the deep regions of the scaffold, and the neovascularization capacity determines the upper limit of the size of living tissue formed within the scaffold. Subsequently, the primary vascular network undergoes remodeling and hierarchical development through splitting, which depends on the response to hemodynamic stress. This is a progressive temporal process, and the developmental capacity of the primary vascular network determines the survival time of this living tissue. Based on this, we propose that engineering interventions be used to provide artificial microenvironmental support in regions and at stages beyond spontaneous vascularization capacity to induce sprouting or facilitate splitting. This way, physiological vascularization of large-scale scaffolds is expected to be achieved.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70170"},"PeriodicalIF":6.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147927187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}