Comprehensive Physiology最新文献

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.

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.

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.

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 (p = 0.004) and hematocrit (p = 0.033). The IL6 C-G-G haplotype (rs1800795-rs1800796-rs1800797) was associated with higher serum-iron (p = 0.0012, within-phenotype FDR-adjusted p = 0.002). TNF-α rs1800629, showed a model-dependent association with lower aerobic fitness classification in grouped analyses (p = 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 (p = 0.037) had higher LDL cholesterol, was not retained in whole-cohort adjusted-analyses. IL15 showed no single-locus effects but an exploratory multi-locus genotype combination, IL15 CC/CT × TNF-α GG, associated with higher odds of aerobic fitness classification (p = 0.004). Whole-cohort analyses: IL6 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. IL6 rs1800795 mainly associated with iron-related and hematological traits; TNF-α rs1800629 findings were model-dependent and inconsistent. IL15 CC/CT × TNF-α GG combination is exploratory, requiring independent replication.

Background: 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.

Methods: 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" (n = 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" (n = 79, HFpEF = 34). Stepwise approach included: physiological groups (tertiles) using exercise PVR cutoff = 1.74 WU and median approach with ∆PVR decrease with exercise.

Results: 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, p = 0.003) and COPD (β-estimate = 1.74, p = 0.03) were significant. However, with multivariate model (including LAVI and TAPSE), COPD remained significant (β-estimate = 3.26, p = 0.02), while atrial fibrillation (β-estimate = 1.60, p = 0.06) and LAVI (β-estimate = 0.05, p = 0.09) approached significance. The unfavorable versus favorable exercise PVR HFpEF subgroups had similar biventricular morphology by cardiac MRI (p < 0.30).

Conclusions: 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.

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.

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.

Objective: 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.

Methods: 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.

Results: 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).

Conclusion: 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.

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.

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.