American journal of physiology. Heart and circulatory physiology最新文献

{"title":"The mechanisms of Chr.9p21.3 risk locus in coronary artery disease: where are we today?","authors":"Anna-Kaisa Ruotsalainen, Sanna Kettunen, Tuisku Suoranta, Minna U Kaikkonen, Seppo Ylä-Herttuala, Rédouane Aherrahrou","doi":"10.1152/ajpheart.00580.2024","DOIUrl":"10.1152/ajpheart.00580.2024","url":null,"abstract":"<p><p>Despite the advancements and release of new therapeutics in the past few years, cardiovascular diseases (CVDs) have remained the number one cause of death worldwide. Genetic variation of a 9p21.3 genomic locus has been identified as the most significant and robust genetic CVD risk marker on the population level, with the strongest association with coronary artery disease (CAD) and other diseases, including diabetes and cancer. Several mechanisms of 9p21.3 in CVDs have been proposed, but their effects on CVDs have remained elusive. Moreover, most of the single nucleotide polymorphisms (SNPs) associated with CAD are located on a sequence of a long noncoding RNA (lncRNA) called <i>ANRIL</i>. <i>ANRIL</i> has several linear and circular splicing isoforms, which seem to have different effects and implications for CVDs. The mechanisms of the 9p21.3 locus and the interplay of its coding and noncoding transcripts in different diseases require further research. Circular RNAs have generally raised interest due to their beneficial features as biomarkers and therapeutic molecules. Here, we review the literature of 9p21.3 from its identification in 2007 and draw the current knowledge on its function, implications in CVDs, and therapeutic potential.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H196-H208"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799013","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":"Prenatal dexamethasone programs autonomic dysregulation in female rats.","authors":"Lakshmi Madhavpeddi, Monique Martinez, Jared Alvarez, Arpan Sharma, Chengcheng Hu, Stuart A Tobet, Taben M Hale","doi":"10.1152/ajpheart.00075.2024","DOIUrl":"10.1152/ajpheart.00075.2024","url":null,"abstract":"<p><p>Autonomic dysfunction is associated with cardiovascular and neurological diseases, including hypertension, heart failure, anxiety, and stress-related disorders. Prior studies demonstrated that late gestation exposure to dexamethasone (DEX) resulted in female-biased increases in stress-responsive mean arterial pressure (MAP) and heart rate (HR), suggesting a role for glucocorticoid-mediated programming of autonomic dysfunction. The present study investigated the influence of sympathetic (SYM) or parasympathetic (PS) blockade on cardiovascular function in male and female rat offspring of mothers injected with DEX in utero [<i>gestation days</i> (GD) <i>18</i>-<i>21</i>]. At 11-12-wk of age, MAP, HR, and heart rate variability (HRV) were evaluated at baseline and in response to SYM antagonists (α₁-adrenoceptor + β₁-adrenoceptor), a PS (muscarinic) antagonist, or saline (SAL). To assess stress-responsive function, rats were exposed to acute restraint. Tyrosine hydroxylase was measured in the adrenals and left ventricle, and expression of the β₁ adrenergic receptor, choline acetyltransferase, and acetylcholinesterase were measured in the left ventricle. Maternal DEX injection reduced basal HRV in male and female offspring. SYM blockade attenuated increases in stress-responsive HR and MAP. PS blockade elevated stress-responsive HR and MAP to a greater extent in vehicle females. SYM and PS blockade produced equivalent effects on HR and MAP responses in male offspring, regardless of maternal treatment. Based on these findings, we suggest that maternal DEX injection disrupted autonomic regulation of cardiovascular function in females, resulting in a shift toward greater SYM input and less input from PS. Future studies will investigate whether changes in autonomic function are mediated by changes in central autonomic circuitry.<b>NEW & NOTEWORTHY</b> Pharmacological antagonists are used to characterize the nature of the autonomic dysregulation induced in female offspring exposed to dexamethasone, in utero. The female offspring of dams injected with dexamethasone in late gestation show a reduction in vulnerability to parasympathetic blockade and an increase in responses to acute restraint stress even in the presence of sympathetic blockade. This suggests that late gestation dexamethasone disrupts the normal development of the autonomic function in females, shifting sympathovagal balance.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H209-H220"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880884","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":"Programming the heart: prenatal glucocorticoids and sex-specific cardiovascular risk.","authors":"Jessica L Caldwell","doi":"10.1152/ajpheart.00884.2024","DOIUrl":"10.1152/ajpheart.00884.2024","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H245-H246"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909032","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":"Hyperglycemia inhibits AAA expansion: examining the role of lysyl oxidase.","authors":"Kathryn E Jespersen, Wanfen Xiong, Lakshmi Santhanam, Michael Terrin, Jon Matsumura, John A Curci, William Blackwelder, Clayton H Brown, Marta Martinez Yus, B Timothy Baxter","doi":"10.1152/ajpheart.00163.2024","DOIUrl":"10.1152/ajpheart.00163.2024","url":null,"abstract":"<p><p>Abdominal aortic aneurysm (AAA) is a common, progressive, and potentially fatal dilation of the most distal aortic segment. Multiple studies with longitudinal follow-up of AAA have identified markedly slower progression among patients affected with diabetes. Understanding the molecular pathway responsible for the growth inhibition could have implications for therapy in nondiabetic patients with AAA. Toward this end, we investigated the effects of hyperglycemia in a murine model of AAA and a carefully monitored cohort of patients with AAA from the Noninvasive Treatment of AAA-Clinical Trial (NTA3CT). In mice with hyperglycemia, AAA growth was inhibited to a similar degree (∼30%) as seen in patients with diabetes. AAA growth correlated inversely to levels of hyperglycemia in mice and patients with AAA. Inhibiting lysyl oxidase (LOX) activity increases aneurysm growth and matrix degradation in this model. Hyperglycemia increased LOX concentration in aortic smooth muscle cells (SMCs) but not in murine AAA tissue. Inhibiting LOX activity completely blocked the growth-inhibitory effect of hyperglycemia. Lysyl oxidase-like 2 (LOXL2), the primary arterial isoform of LOX, is expressed in the same area as type IV collagen along the outer media in murine AAA tissue. There is a significant inverse correlation between LOXL2 and AAA growth rates in patients. Taken together, these studies suggest a role for LOXL2-mediated type IV collagen crosslinking in slowing AAA growth in the setting of hyperglycemia.<b>NEW & NOTEWORTHY</b> AAA grows slower in patients affected by diabetes. This growth inhibition is lost when the enzyme lysyl oxidase (LOX) is blocked in diabetic mice. The predominant arterial isoform of LOX, LOX-like 2 (LOXL2), overlaps with type IV collagen in the outer media of murine aneurysm tissue. Circulating LOXL2 correlates inversely with AAA growth in patients. Type IV collagen cross-linking by LOXL2 may play a role in the AAA growth inhibition associated with diabetes.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H247-H259"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880882","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":"A novel method for the measurement of cardiovascular responses to lower body negative pressure in the awake instrumented rat.","authors":"Michelle L Nieman, Samuel R Lorenz, John N Lorenz","doi":"10.1152/ajpheart.00830.2024","DOIUrl":"10.1152/ajpheart.00830.2024","url":null,"abstract":"<p><p>Lower body negative pressure (LBNP) has been used for decades in humans to model arterial baroreceptor unloading and represents a powerful tool for evaluating cardiovascular responses to orthostatic challenges. However, LBNP studies in animals have been limited to conditions of anesthesia or sedation, where cardiovascular reflexes are altered. Given the consequent uncertainties, the usefulness of LBNP studies in these preclinical models has been severely hampered. Here, we developed an approach using a novel system to study LBNP responses in awake rats instrumented for telemetric blood pressure (BP) measurement. BP responses to progressive levels of LBNP (-3 to -15 mmHg) were first made in awake rats, followed by measurements under various treatments. In awake untreated rats, BP was well maintained up to -15 mmHg LBNP and there was a robust baroreceptor response in heart rate (HR). Under anesthesia with 3% isoflurane, BP was not maintained at LBNP below -3 mmHg and baroreceptor responses in HR were completely blocked, confirming the limited usefulness of this method under anesthesia. Interrogation of the autonomic pathways involved in the response revealed that muscarinic (atropine) and β₁-adrenergic (atenolol) blockade, separately or together, blocked the HR responses, but BP remained well maintained. α₁-adrenergic blockade (prazosin) severely blunted the ability to maintain BP in response to LBNP. These data are consistent with findings in human subjects in that the vascular component of the orthostatic reflex predominates in preserving BP. Validation of this novel method provides a valuable tool for investigating orthostatic (in)tolerance in a facile preclinical model.<b>NEW & NOTEWORTHY</b> Orthostatic hypotension or intolerance is a common but often underappreciated disorder that is associated with a variety of neurological comorbidities. LBNP studies provide a valuable tool to study these conditions, but heretofore could only be used in human subjects, since animal subjects needed to be anesthetized or sedated, which blunts or eliminates neurocardiovascular reflexes. This novel method allowing LBNP studies in awake rats will provide a valuable preclinical model for studying these disorders.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H310-H322"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942648","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":"Heart and health behavior responses to GLP-1 receptor agonists: a 12-wk study using wearable technology and causal inference.","authors":"Gregory J Grosicki, Jeongeun Kim, Finn Fielding, Summer R Jasinski, Christopher Chapman, William von Hippel, Kristen E Holmes","doi":"10.1152/ajpheart.00809.2024","DOIUrl":"10.1152/ajpheart.00809.2024","url":null,"abstract":"<p><p>Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were originally developed for the treatment of type 2 diabetes but have recently been approved for chronic weight management and reducing cardiovascular risk in individuals with overweight and obesity. Despite this approval, significant heterogeneity in the cardioprotective benefits and less desirable increases in resting heart rate (RHR) with GLP-1 RAs have been reported. To better understand cardiovascular responses to GLP-1 RAs and the potential role of health behaviors in influencing these responses, we leveraged wearable technology and causal inference analysis. We tracked RHR, heart rate variability (HRV), physical activity, and sleep in 66 individuals (42 ± 9 yr, body mass index: 30.0 ± 7 kg/m²) from the week before to 12 wk following the initiation of GLP-1 RA medication. Propensity score matching on a larger sample of wearable users identified a control group with similar anthropometric and cardiovascular characteristics (<i>P</i>s > 0.26). After the 12-wk study period, GLP-1 users showed significant (<i>P</i>s < 0.05) weight loss (-10.0%, 95% CI: -11.2% to -8.5%) and changes in RHR (3.2 ± 0.8 beats/min) that were mediated (<i>P</i> < 0.01) by changes in HRV (-6.2 ± 1.4 ms) compared with control. Trends (<i>P</i>s < 0.10) suggested that increases in weekly physical activity were associated with GLP-1 RA medication (31.5 ± 13.2 min) and that higher physical activity levels accompanied an attenuation of RHR increases. Our real-world findings align with clinical trial data in showing rapid and significant weight loss with GLP-1 RAs, coinciding with increases in RHR that are mediated by changes in autonomic function (i.e., HRV). Physical activity may help to offset RHR increases, but further research is needed to confirm these effects.<b>NEW & NOTEWORTHY</b> These findings are among the first to provide daily insights into cardiovascular and behavioral responses following GLP-1 RA initiation. Substantial weight loss and significant increases in resting heart rate mediated by reductions in heart rate variability during the initial 12 wk of GLP-1 RA therapy were observed. In addition, trends suggest an increase in physical activity with GLP-1 therapy, and that physical activity may help to temper GLP-1 RA-associated increases in resting heart rate.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H235-H241"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142869287","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":"Lab-grown, 3D extracellular matrix particles improve cardiac function and morphology in myocardial ischemia.","authors":"Mark Broadwin, Katerina St Angelo, Max Petersen, Rayane B Teixeira, Dwight D Harris, Christopher R Stone, Cynthia Xu, Meghamsh Kanuparthy, Frank W Sellke, Jeffrey Morgan, M Ruhul Abid","doi":"10.1152/ajpheart.00581.2024","DOIUrl":"10.1152/ajpheart.00581.2024","url":null,"abstract":"<p><p>The promise of injection of extracellular matrix (ECM) from animal hearts as a treatment of myocardial ischemia has been limited by immune reactions and harsh ECM-damaging extraction procedures. We developed a novel method to produce lab-grown human three-dimensional (3-D) acellular ECM particles from human mesenchymal stem cells (MSCs) to mitigate product variability, immunogenicity, and preserve ECM architecture. We hypothesized that intramyocardial injection (I/M) of this novel ECM (dia ∼ 200 microns) would improve cardiac function in a postmyocardial infarction (MI) murine model. WT mice aged 8-10 wk underwent ligation of the left anterior descending coronary (LAD) artery and I/M injection of 10 μL ECM or normal saline (<i>n</i> = 10/group). Compared with control, ECM-treated hearts showed significant reduction in infarct size (<i>P</i> = 0.04), increased capillary density in ischemic myocardium (<i>P</i> = 0.01), and increased fractional shortening (FS) (<i>P</i> < 0.05) on <i>postoperative days</i> (POD) <i>14</i>, <i>21</i>, and <i>28</i> by echocardiography. There were no significant differences in immunogenic response as determined by TNFα, IL6, CD86, or CD163 levels (<i>P</i> > 0.05 for all) in the hearts. Biodistribution of fluorophore-conjugated ECM demonstrated localized epifluorescence in the heart after I/M injection, without significant peripheral end organ epifluorescence. Proteomic analysis of ischemic and perfused myocardium from control and ECM-treated hearts using LC-MS/MS (<i>n</i> = 3/group) detected significant changes in proteins involved in cardiomyocyte contractility and fatty acid metabolism. These findings suggest that 3-D ECM particles induce recovery of ischemic myocardium, by upregulating protein networks involved in cellular contractility and metabolism. Taken together, 3-D ECM particles represent a promising therapy for MI and warrant confirmatory studies in a high-fidelity large animal model.<b>NEW & NOTEWORTHY</b> Our novel lab-grown, human 3-D extracellular matrix (ECM) represents a novel therapeutic approach to prevent pathological remodeling and heart failure in an animal model of heart attack. This novel finding may help develop nonsurgical therapeutic modalities aimed at reducing the global burden of cardiovascular disease.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H221-H234"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142869288","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":"A minimally invasive swine model of chronic kidney disease-associated heart failure.","authors":"Spyros A Mavropoulos, Tadao Aikawa, Renata Mazurek, Tomoki Sakata, Kelly Yamada, Kenji Watanabe, Genya Sunagawa, Samta Veera, Deanndria T Singleton, Kyra Leonard, Taro Kariya, Susmita Sahoo, Kiyotake Ishikawa","doi":"10.1152/ajpheart.00449.2024","DOIUrl":"10.1152/ajpheart.00449.2024","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) is on the rise, and over 50% of patients die from cardiac causes. Patients develop heart failure due to unelucidated reno-cardiac interactions, termed type 4 cardiorenal syndrome (CRS4). The aim of this study is to establish and characterize a reliable model of CRS4 in swine with marked cardiac diastolic dysfunction. Yorkshire pigs (19.9 ± 1.7 kg, 4 females and 5 males) underwent staged renal artery embolization using autologous clot. Echocardiogram, aortic pressure (AoP), renal angiogram, and blood samples were assessed monthly. At 4 mo, animals were euthanized after measuring glomerular filtration rate (GFR) and left ventricular (LV) pressure-volume parameters. Heart and kidneys were collected for postmortem analyses. Size-matched swine (<i>n</i> = 5; 43.7 ± 9.8 kg) served as controls. After three dose-titrated renal embolization, serum creatinine (SCr) and AoP increased by wk 10. At 4 mo, SCr (2.03 ± 0.45 vs. 1.34 ± 0.17 mg/dL, <i>P</i> = 0.013) and AoP (158 ± 16 vs. 121 ± 8 mmHg, <i>P</i> = 0.001) were higher, and GFR was lower (12 ± 3 vs. 131 ± 7 mL/min, <i>P</i> < 0.001) than size-matched controls. Although the LV ejection fraction was similar, the slope of the end-diastolic pressure-volume relationship was steeper in pigs after renal embolization (0.36 ± 0.09 vs. 0.17 ± 0.06, <i>P</i> = 0.003), indicating increased LV stiffness. LV mass index (2.73 ± 0.19 vs. 2.50 ± 0.13 g/kg, <i>P</i> = 0.043) and wall-thickness (11.4 ± 0.8 vs. 8.9 ± 1.2 mm, <i>P</i> = 0.003) increased. These were accompanied by histologically increased fibrosis, cardiomyocyte hypertrophy, and vascular rarefaction. Repeat titrated renal embolization resulted in a model that exhibits advanced CKD and cardiac abnormalities consistent with CRS4.<b>NEW & NOTEWORTHY</b> Cardiac pathological changes consistent with heart failure with preserved ejection fraction can be induced in a large animal model by serial and titrated renal embolization of kidneys with autologous clot, leading to severe renal dysfunction and impaired cardiac diastolic function.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H260-H270"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880877","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":"A heavy burden: unraveling the consequences of perinatal iron deficiency on offspring heart health.","authors":"Jennifer J Gardner, Jessica L Bradshaw","doi":"10.1152/ajpheart.00860.2024","DOIUrl":"10.1152/ajpheart.00860.2024","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H242-H244"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880876","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":"Endothelial cell-selective adhesion molecule deficiency exhibits increased pulmonary vascular resistance due to impaired endothelial nitric oxide signaling.","authors":"Vadym Buncha, Liwei Lang, Katie Anne Fopiano, Daria V Ilatovskaya, Gaston Kapuku, Alexander D Verin, Zsolt Bagi","doi":"10.1152/ajpheart.00593.2024","DOIUrl":"10.1152/ajpheart.00593.2024","url":null,"abstract":"<p><p>Endothelial cell-selective adhesion molecule (ESAM) is a member of tight junction molecules, highly abundant in the heart and the lung, and plays a role in regulating endothelial cell permeability. We previously reported that mice with genetic ESAM deficiency (<i>ESAM</i>^-/-) exhibit coronary microvascular dysfunction leading to the development of left ventricular diastolic dysfunction. Here, we hypothesize that <i>ESAM</i>^-/- mice display impairments in the pulmonary vasculature, affecting the overall pulmonary vascular resistance (PVR). We utilized <i>ESAM</i>^-/- mice and employed isolated, ventilated, and perfused whole lung preparation to assess PVR independently of cardiac function. PVR was assessed in response to stepwise increases in flow, and also in response to perfusion of the endothelium-dependent agonist, bradykinin, the thromboxane analog, U46619, and the nitric oxide (NO) donor sodium nitroprusside (SNP). We found that PVR, at every applied flow rate, is significantly elevated in <i>ESAM</i>^-/- mice compared with WT mice. Bradykinin-induced reduction in PVR and U46619-induced increase in PVR were both diminished in <i>ESAM</i>^-/- mice, whereas SNP-induced responses were similar in wild-type (WT) and <i>ESAM</i>^-/- mice. Inhibition of NO synthase with <i>N</i>(ω)-nitro-l-arginine methyl ester increased agonist-induced PVR in WT but not in <i>ESAM</i>^-/- mice. Pulmonary arteries isolated from <i>ESAM</i>^-/- mice exhibited a reduced level of phospho-Ser473-Akt and phospho-Ser1177-eNOS. Furthermore, in human lung microvascular endothelial cells cultured under flow conditions, we found that siRNA-mediated knockdown of ESAM impaired fluid shear stress-induced endothelial cell alignment. Thus, we suggest that ESAM plays an important role in the endothelium-dependent, flow/shear stress- and vasoactive agonist-stimulated, and NO-mediated maintenance of PVR in mice.<b>NEW & NOTEWORTHY</b> Our study reveals a novel role for ESAM in contributing to the maintenance of pulmonary vascular resistance under normal physiological conditions. Employing mice with global genetic deficiency of ESAM and using isolated whole lung preparation, we show significant impairments in nitric oxide-mediated pulmonary artery function. In vitro cell culture studies demonstrate impaired fluid shear stress-induced cell alignment in human lung endothelial cells after siRNA-mediated ESAM knockdown.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H283-H293"},"PeriodicalIF":4.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909017","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}