Comprehensive Physiology最新文献

{"title":"Oxysterol Signaling Within the Microbiome-Regulated Gut-Liver-Brain Axis: Implications for Metabolic Homeostasis and Neurodegeneration.","authors":"Nila Ganamurali, Sarvesh Sabarathinam","doi":"10.1002/cph4.70181","DOIUrl":"10.1002/cph4.70181","url":null,"abstract":"<p><p>The gut-liver-brain axis integrates metabolic and inflammatory signals that influence systemic homeostasis and cognitive function. While current models emphasize short-chain fatty acids and bile acids, they do not fully explain lipid-driven neurodegenerative processes. Oxysterols, oxidized derivatives of cholesterol, are emerging as key signaling molecules that bridge peripheral metabolism and brain function. Generated at the gut-liver interface through enzymatic and oxidative pathways, oxysterols regulate lipid and glucose metabolism via nuclear receptors, including liver X receptors and farnesoid X receptor. Importantly, specific oxysterols cross the blood brain barrier, enabling bidirectional communication between the periphery and central nervous system. By modulating neuroinflammation and synaptic function, oxysterols provide a mechanistic link between metabolic dysfunction and cognitive decline.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70181"},"PeriodicalIF":6.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148013913","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":"Integrating ΔPCO₂ and Ca-vO₂ Into a Heart-Lung Coupling Index: A Novel Approach to Evaluate Cardiopulmonary Uncoupling in Pulmonary Arterial Hypertension.","authors":"Ashfaq Ahmad, Songlin Zhang, Qian Ren, Lingling Li, Yajuan Du, Xiaoyu Wang, Ting Liu, Ekhlas Mahmoud Al-Hashedi, Fenling Fan","doi":"10.1002/cph4.70148","DOIUrl":"10.1002/cph4.70148","url":null,"abstract":"<p><strong>Aim: </strong>To evaluate arterio-venous gas parameters-P(ca-v)CO₂ or ΔPCO₂, Ca-vO₂, and P(v-a) CO₂/Ca-vO₂ ratio, and to develop a novel Heart-Lung Coupling (HLC) index defined as (ΔPCO₂/Ca-vO₂)/Cardiac Index to quantify the interaction between ventilatory efficiency and circulatory performance in pulmonary arterial hypertension (PAH).</p><p><strong>Methods: </strong>In this single-center retrospective study, patients with PAH who underwent right heart catheterization between September 2019 and May 2024 were evaluated. After exclusions, 115 patients were included (35 idiopathic PAH [IPAH] and 80 congenital heart disease-associated PAH [CHD-PAH]). Hemodynamics, arteriovenous gas parameters, and functional indices, including 6-min walk distance (6MWD) and NT-proBNP, were analyzed. The HLC was calculated and compared between groups. Association with functional parameters was assessed using Spearman correlation and multivariate linear regression after LASSO selection. Receiver operating characteristic analysis evaluated the ability of HLC to identify impaired exercise capacity (6MWD < 350 m).</p><p><strong>Results: </strong>ΔPCO₂, Ca-vO₂ and P(v-a) CO₂/Ca-vO₂ ratio were significantly higher in IPAH than CHD-PAH (8.3 vs. 3.5 mmHg, p < 0.001; 4.8 vs. 3.4 mL/dL, p = 0.005; 1.84 vs. 1.11, p < 0.001, respectively). The HLC index was also higher in IPAH (median 0.82 vs. 0.40, p = 0.001). HLC showed modest correlation with 6MWD (r = 0.27, p = 0.04) and NT-proBNP (r = 0.24, p = 0.021). In multivariate regression, HLC remained independently associated with 6MWD (β = 32.86, 95% CI: 5.15-60.57, p = 0.021). Discrimination of impaired exercise capacity was limited (AUC of 0.55).</p><p><strong>Conclusion: </strong>The HLC index integrates gas exchange and cardiac output to characterize heart-lung interaction in PAH. This novel physiological metric may provide complementary insights into cardiopulmonary coupling and functional limitation.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70148"},"PeriodicalIF":6.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764222","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":"GDNF Maintains Mitochondrial Homeostasis and Inhibits Ferroptosis to Improve Osteogenic Function in Osteoporosis.","authors":"Yafei Zhu, Runhan Zhao, Yingtao Duan, Yukun Jia, Zhou Xie, Xiao Qu, Dagang Tang, Yanran Huang, Xiaoji Luo","doi":"10.1002/cph4.70172","DOIUrl":"10.1002/cph4.70172","url":null,"abstract":"<p><p>Osteoporosis is a metabolic bone disease characterized by reduced bone mass and deterioration of bone microarchitecture, in which impaired osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) represents a central pathological mechanism. In recent years, ferroptosis, a newly recognized form of regulated cell death, has been demonstrated to play an important role in the initiation and progression of osteoporosis. Mitochondrial dysfunction can exacerbate oxidative stress and disrupt iron metabolism, thereby triggering ferroptosis in BMSCs and ultimately inhibiting osteogenic differentiation. The present study aimed to identify and validate key genes associated with mitochondrial homeostasis and osteoporosis, with a particular focus on the role of glial cell line-derived neurotrophic factor (GDNF) in regulating mitochondrial function, suppressing ferroptosis, and promoting osteogenic differentiation of BMSCs. Gene expression data from normal human bone tissues and osteoporotic bone tissues were obtained from public transcriptomic datasets in the Gene Expression Omnibus (GEO) database. Through differential expression analysis, GDNF was identified as a candidate gene. In vitro experiments demonstrated that GDNF markedly improved mitochondrial membrane potential, reduced intracellular reactive oxygen species (ROS) levels, and restored GPX4 expression, thereby promoting osteogenic differentiation of BMSCs. Furthermore, animal experiments confirmed that GDNF intervention effectively increased bone mineral density and improved trabecular microarchitecture in ovariectomized (OVX) mice. In conclusion, this study identified GDNF may suppress ferroptosis by maintaining mitochondrial homeostasis in BMSCs, thereby enhancing osteogenic differentiation and alleviating osteoporosis, providing a potential theoretical basis for molecular targeted therapy in osteoporosis.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70172"},"PeriodicalIF":6.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147927138","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":"Evaluating Anesthetics for Improving Scientific Research and Welfare Using Larval Zebrafish.","authors":"Sylvia Dimitriadou, Mhairi Miller, Ali Pilehvar, Lynne U Sneddon, Jessica L Bamsey, Damilola Hogan-Bassey, Maciej Trznadel, Jonathan S Ball, Aya Takesono, Courtney Hillman, Hannah Rickard, Grace Popplewell, Jenna Corcoran, Tetsuhiro Kudoh, Charles R Tyler, Matthew J Winter","doi":"10.1002/cph4.70174","DOIUrl":"10.1002/cph4.70174","url":null,"abstract":"<p><p>Establishing anesthesia for ensuring both animal welfare and compatibility with protocols required for different areas of scientific research is vital. Zebrafish (Danio rerio) are one of the most used animal models in research; however, little is known about appropriate anesthetic use in this species, especially for embryo-larval life stages. Using a combination of whole-brain functional imaging, quantification of cardiovascular performance, and behavior, we explore the efficacy and tolerability of six widely used fish anesthetics (2-phenoxyethanol, benzocaine, etomidate, MS222, isoeugenol, and quinaldine sulfate) in larval zebrafish. We show that MS222 and quinaldine sulfate are the most suitable for achieving deep anesthesia, whereas etomidate is better suited for studies focused on the cardiovascular system. Only quinaldine sulfate was found to be aversive. Our findings aid researchers to select the most suitable anesthetic compounds and concentrations for their specific research goals, and the refinement of studies using anesthesia in larval zebrafish.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70174"},"PeriodicalIF":6.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147971242","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":"Interplay Between the Gut-Microbiota-Brain Axis and the Immune System in Viral Neuroinvasion and CNS Pathogenesis.","authors":"Anirudh Satheesan, Shivangi Sharma, Mayghaa Chatterjee, Anirban Basu","doi":"10.1002/cph4.70186","DOIUrl":"10.1002/cph4.70186","url":null,"abstract":"<p><p>Evolving demographic factors have contributed to the continuous emergence of viral pathogens in humans, a great portion of which target the central nervous system (CNS). These viral pathogens influence multiple layers of host physiology, including the host's microbial communities. Gut microbiota consist of a plethora of microscopic organisms that serve as an integral part of the gut-brain axis. Emerging evidence suggests that the microbiota-gut-brain axis regulates many physiological processes, which are critical to the disease outcome, such as the immune response in several viral infections. Numerous researchers have examined the physiological and pathophysiological mechanisms potentially influenced by the gut microbiota in several CNS disorders and viral infections. Knowledge of the biological interactions between these pathogens and the host physiological system provides us with the opportunity to mitigate the infection while at the same time preparing for the inevitable outcome of the disease. This article reviews up-to-date evidence on the correlation between the gut-brain-immune axis and neurotropic viral infections.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70186"},"PeriodicalIF":5.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148142925","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":"SLC16A9-Mediated Carnitine Uptake Enhances Radiotherapy Resistance in Colorectal Cancer via Lipid Metabolic Reprogramming.","authors":"Meng Wang, Jian Tang, Xing Wen, Jianhui Gu, Jie Zhang, Yuanchuan Zhang, Liping Wu","doi":"10.1002/cph4.70184","DOIUrl":"10.1002/cph4.70184","url":null,"abstract":"<p><strong>Background: </strong>Radiation resistance severely impairs the therapeutic efficacy of radiotherapy in colorectal cancer (CRC). Lipid metabolic reprogramming, particularly the activation of fatty acid oxidation (FAO), has been well recognized to be closely implicated in radioresistance, whereas its underlying regulatory mechanism remains poorly elucidated. This study aimed to explore the functional role of the transporter SLC16A9 in CRC radioresistance and its correlation with carnitine metabolism as well as the FAO signaling pathway.</p><p><strong>Methods: </strong>Differentially expressed genes associated with radioresistance were screened by analyzing public transcriptomic databases and further validated using clinical specimens. CCK-8 assay, colony formation assay, comet assay, and cell apoptosis analysis were performed to evaluate cellular radiosensitivity. RT-qPCR, Western blot, and immunofluorescence staining were adopted to detect SLC16A9 expression levels and DNA damage status. Metabolic flux analysis, ATP measurement, and radioactive carnitine uptake assay were utilized to assess carnitine uptake capacity and FAO activity. A nude mouse xenograft tumor model was constructed to determine the in vivo influence of SLC16A9 on tumor response to radiotherapy.</p><p><strong>Results: </strong>Elevated expression of SLC16A9 was observed in radioresistant CRC cell lines and clinical samples. SLC16A9 facilitated carnitine uptake and augmented FAO pathway activity, which was accompanied by reduced radiation-induced DNA damage, decreased reactive oxygen species (ROS) levels, and enhanced cellular survival capability. Inhibition of FAO partially reversed the above biological effects. In the in vivo model, upregulated SLC16A9 was correlated with attenuated tumor suppression efficacy of radiotherapy, while SLC16A9 inhibition markedly elevated radiosensitivity.</p><p><strong>Conclusion: </strong>SLC16A9 contributed to the development of CRC radioresistance by promoting carnitine uptake and enhancing FAO activity. This study provided novel evidence supporting the association between metabolic reprogramming and radiosensitivity and suggested that targeting SLC16A9 or the FAO pathway held promising potential for clinical therapeutic application.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70184"},"PeriodicalIF":5.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148216756","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":"Cardiovascular β-Adrenergic Receptor Distribution and Function: Influence of Species, Sex, Age, and Tissue.","authors":"Basant Elsaid, Irakli Kopaliani, Birgit Zatschler, Ansam Seif, Stephan Speier, Andreas Deussen","doi":"10.1002/cph4.70159","DOIUrl":"10.1002/cph4.70159","url":null,"abstract":"<p><p>Cardiovascular diseases remain the leading global cause of morbidity and mortality, with notable sex-specific differences in prevalence and outcomes. Increasing evidence indicates that β-adrenergic receptors (β-AR) play a central role in cardiovascular regulation and that their expression, signaling, and responsiveness are modulated by estrogen. However, the precise mechanisms underlying β-AR-estrogen interactions remain incompletely defined and highly context dependent. This mini-review summarizes current knowledge of β-AR subtypes, their cardiovascular distribution, and their signaling pathways, emphasizing how estrogen influences β-AR function across species, sexes, ages, and cardiovascular tissues. Comparative analysis of data reveals substantial heterogeneity arising from tissue specificity, receptor subtype composition, and experimental models. These differences underscore the challenges of translating preclinical findings into human physiology. Future studies integrating multi-species and sex-specific approaches, including the development of genetic knockout models and validation using human vascular cells, are essential to bridge mechanistic insights with clinical relevance. Understanding the interplay between β-AR signaling and estrogen is key to developing sex-specific strategies for the prevention and treatment of cardiovascular diseases.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70159"},"PeriodicalIF":6.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13128987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764245","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":"Oxygen Supplementation Improves Oxygen Uptake Kinetics and Exercise Performance in PAH and CTEPH Patients.","authors":"Shir Kadosh, Yael Baidats, Andrew M Jones, Daryl Wilkerson, Ariela Velner, Ronen Reuveny, Michael J Segel","doi":"10.1002/cph4.70194","DOIUrl":"10.1002/cph4.70194","url":null,"abstract":"<p><strong>Aim: </strong>We studied the effect of O₂ supplementation on physiological responses to exercise in patients with pulmonary vascular disease.</p><p><strong>Methods: </strong>Six patients with pulmonary arterial hypertension (PAH), four patients with chronic thromboembolic pulmonary hypertension (CTEPH) (age 54 ± 17 years; 8 females) and 13 healthy individuals (age 50 ± 17 years; 5 females) were tested. PAH/CTEPH was defined hemodynamically by mPAP > 20 mmHg and PVR > 3 WU. Patients performed symptom-limited cardiopulmonary exercise tests, and constant work-rate tests (CWRTs) at 80% of the work-rate (WR) at the gas exchange threshold (GET). Tests breathing room air (RA, 21% O₂) were compared to tests performed breathing 30% O₂. Oxygen-uptake (V̇O₂) kinetics were calculated from the CWRT results.</p><p><strong>Results: </strong>In the PAH/CTEPH group, peak WR, peak V̇O₂ and V̇O₂ at the GET improved significantly when breathing 30% O₂ compared to RA (mean ± SD 85 ± 26 vs. 77 ± 25 W, 18.3 ± 5.8 vs. 15.6 ± 5.7 mL/kg/min and 764 ± 181 vs. 685 ± 154 mL/min; p = 0.011, p = 0.015 and p = 0.012, respectively). Peak V̇O_2/HR was higher with 30% O₂ compared with RA (8.8 ± 2.2 vs. 7.7 ± 1.8 mL/beat, p = 0.021). The time constant (tau) of V̇O₂ kinetics was faster in PAH/CTEPH patients while breathing 30% O₂ compared to RA (36 ± 4 vs. 43 ± 6 s, p = 0.009). In healthy individuals there was no improvement in V̇O₂ kinetics while breathing 30% O₂ compared to RA (tau 35 ± 6 vs. 35 ± 6 s, p = 0.916).</p><p><strong>Conclusion: </strong>A clinically applicable level of O₂ supplementation (30%) improved maximal and aerobic exercise capacity and V̇O₂ kinetics in PAH/CTEPH patients. O₂ supplementation may be considered to support exercise training in PAH/CTEPH patients.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70194"},"PeriodicalIF":6.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13260875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148223589","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":"Autophagy as a Redox Rheostat Linking Cigarette Smoke, Electronic Cigarettes, and Nicotine Exposure to Lung Development, Disease, and Interorgan Communication.","authors":"Noushin Lotfi, Nahid Rezaei, Gourav Chandan, Omid Akbari, Virender K Rehan","doi":"10.1002/cph4.70167","DOIUrl":"10.1002/cph4.70167","url":null,"abstract":"<p><p>Autophagy is a central cellular quality-control pathway that maintains metabolic and proteostatic homeostasis by degrading damaged organelles and proteins. In the lung, autophagy contributes to normal development, epithelial integrity, mitochondrial quality control, and immune regulation. Emerging evidence indicates that environmental exposures such as cigarette smoke (CS), electronic cigarette (EC) aerosols, and nicotine profoundly disrupt these processes, contributing to both chronic lung disease and developmental programming of respiratory pathology. In this review, we propose a unifying framework in which autophagy functions as a redox-modulated rheostat that integrates oxidative, metabolic, and epigenetic stress signals triggered by smoke and nicotine exposure. Under physiological conditions, autophagy mitigates oxidative stress by removing dysfunctional mitochondria and maintaining proteostasis. However, chronic exposure to CS or EC aerosols generates excessive reactive oxygen species, impairs lysosomal degradation, and disrupts mitochondrial quality control, shifting autophagy from an adaptive protective response to a maladaptive driver of epithelial injury, inflammation, and tissue remodeling. Integrating experimental and clinical evidence, we identify four mechanistic axes underlying smoke-induced autophagy dysregulation: lysosomal dysfunction with TFEB suppression, mitochondrial redox amplification, disruption of selective autophagy pathways (including mitophagy, ER-phagy, xenophagy, and lipophagy), and immune polarization associated with inflammasome activation and cellular senescence. Importantly, maternal smoke and EC exposure similarly perturb autophagy in the placenta and fetal lung, altering developmental trajectories and increasing susceptibility to asthma and chronic lung disease. Viewing autophagy as a dynamic, redox-sensitive rheostat highlights new therapeutic opportunities to restore autophagic flux, lysosomal competence, and mitochondrial quality control in smoke- and nicotine-related lung disease.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70167"},"PeriodicalIF":6.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13245673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856064","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":"Exposure Pattern Determines Methamphetamine-Induced Right Ventricular Dysfunction and Vascular Remodeling.","authors":"Ashok Kumar, Aatish Mahajan, Balaji Krishnamachary, Ling Chen, Navneet K Dhillon","doi":"10.1002/cph4.70191","DOIUrl":"10.1002/cph4.70191","url":null,"abstract":"<p><p>Methamphetamine (MA) use is a recognized risk factor for drug-associated pulmonary arterial hypertension (PAH), yet mechanisms driving methamphetamine-associated PAH (MA-PAH) remain unclear due to the lack of reproducible animal models demonstrating hemodynamic changes. This study aimed to develop a rat model of MA-PAH that reflects human patterns of MA abuse. Male Wistar rats received methamphetamine (MA, 5 mg/kg, i.p.) for 8 weeks using either a chronic daily regimen or a binge-and-crash regimen. Chronic MA administration resulted in a significant reduction in mean arterial pressure and an increase in RV systolic pressure, while ejection fraction and the Fulton index remained unchanged. In contrast, binge-crash MA exposure led to significant RV dilation, reduced RV ejection fraction, elevated RV systolic pressure, and increased RV hypertrophy. Both regimens induced pulmonary arterial medial thickening driven by smooth muscle hyperplasia; however, the binge-and-crash model exhibited more severe remodeling, including enhanced distal muscularization, sporadic endothelial proliferation, and vascular rarefaction. HMGB1 levels were significantly elevated in plasma and pulmonary microvascular endothelial cells isolated from binge-crash MA rats. In vitro, MA treatment induced HMGB1 release from endothelial cells through sigma-1 receptor signaling. Conditioned media from MA-treated endothelial cells stimulated smooth muscle cell proliferation, an effect abolished by HMGB1 neutralization. In conclusion, these findings demonstrate that binge-and-crash MA exposure produces a robust and clinically relevant PAH phenotype and identify HMGB1 as a potential mechanistic contributor linking MA exposure patterns to endothelial-smooth muscle interactions in PAH pathogenesis.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":"16 3","pages":"e70191"},"PeriodicalIF":6.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13238407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148162099","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}