American journal of physiology. Cell physiology最新文献

{"title":"Housing mice in thermoneutrality causes peripheral tissue-specific changes in the number, identity, and phase of circadian-expressed mRNA transcripts.","authors":"Abhilash Prabhat, Shrishti Naidu, Isabel G Stumpf, Emma J Clemons, Ezekiel Rozmus, Samuel O Nwadialo, Yuan Wen, Karyn A Esser, Elizabeth A Schroder, Brian P Delisle","doi":"10.1152/ajpcell.90107.2026","DOIUrl":"https://doi.org/10.1152/ajpcell.90107.2026","url":null,"abstract":"<p><p>Laboratory mice are typically housed at room temperature (20-25°C), well below their thermoneutral zone (about 30°C), imposing chronic mild cold stress that increases metabolic rate by 30-40%. Because circadian and metabolic physiology are highly temperature-sensitive, we tested whether this housing condition reshapes rhythmic gene expression in tissues central to cardiovascular and metabolic health. We hypothesized that mild cold stress suppresses circadian gene expression in peripheral tissues. We performed RNA sequencing on hearts, livers, and diaphragms collected every 4 hours over 48 hours in constant darkness from male mice to identify transcripts with approximately 24-hour rhythms. Thermoneutral housing reorganized the circadian transcriptome tissue-specifically. Out of ∼13000 filtered transcripts, the proportion of rhythmic transcripts (q<0.05) in the heart nearly quadrupled, from 11% (1410) at room temperature to 42% (5282) at thermoneutrality, while the diaphragm rose modestly (6% to 9%; 792 vs. 1153). The liver's overall proportion was unchanged (36% vs. 37%; 4041 vs. 4150), yet more than 30% of rhythmic transcripts were unique between housing conditions. Almost 80% of rhythmic genes in the heart under thermoneutrality show acrophase near the subjective activity/rest transition. Gene ontology analysis revealed coordinated changes in the temporal organization of metabolic pathways in the heart and liver but less pronounced in the diaphragm. These changes occurred without detectable changes in core clock expression, implicating regulators acting downstream of, or parallel to, the clock itself. Because room temperature housing is standard across biomedical research, our findings show that this overlooked variable can distort the circadian transcriptome of tissues central to cardiovascular and metabolic disease, with implications for how mouse studies model human physiology.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149369835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Right heart remodeling in Sugen/hypoxia rat model of severe pulmonary hypertension.","authors":"Veronika Olejnickova, Alena Kvasilova, Priyanka Naidu, Nikhil Perera, Martina Gregorovicova, Martin Bartos, Matus Miklovic, Vojtěch Melenovský, Pavel Talacko, František Papoušek, Jaroslav Hrdlička, Adam Eckhardt, Frantisek Kolar, David Sedmera","doi":"10.1152/ajpcell.90222.2026","DOIUrl":"https://doi.org/10.1152/ajpcell.90222.2026","url":null,"abstract":"<p><p>Pulmonary hypertension (PH) directly impacts the right heart through pressure overload. Unlike well-characterized remodeling of the left ventricle in systemic hypertension, PH-induced changes in the right heart are less understood. Here, we investigate chamber-specific alterations in the right atrium (RA) and right ventricle (RV) in a rat model of PH. PH was induced in 6-week-old male Wistar rats using Sugen/hypoxia (SuHx) treatment. Right heart pressure overload was confirmed by catheterization. Cardiac remodeling was characterized by using confocal microscopy, micro-CT, optical mapping, and proteomic mass spectrometry. The increase in right-heart mass was predominantly attributable to cardiomyocyte hypertrophy, with concomitant extracellular-matrix remodeling. Hypertrophy was associated with significantly elevated right heart pressures after SuHx treatment, further progressing during the subsequent normoxia. At the end of the PH protocol, electrophysiology analysis showed significant prolongation of the action potential in both the RA and RV. Proteomic analysis revealed pronounced alterations in the RV, with substantial overlap with the RA and LV, and more upregulated than downregulated proteins. GO analysis indicated increased expression of sarcomeric and fibrillar proteins and reduced expression of proteins related to oxidative energy production. In conclusion, myocardial remodeling in PH is based on cardiomyocyte hypertrophy rather than cell proliferation. Electrophysiological changes along with increased pressure in the right atrium might contribute to phenotype progression. Changes in proteome show commonalities and differences in RA and RV pressure-induced pathways that that warrant therapeutic exploration.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149340340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond ATP Synthesis: The Proton Motive Force as a Shared Energetic Resource in Mammalian Mitochondria.","authors":"Jarrod A Call, Junwon Heo, Edmund R S Kunji, Kelsey H Fisher-Wellman","doi":"10.1152/ajpcell.90010.2026","DOIUrl":"https://doi.org/10.1152/ajpcell.90010.2026","url":null,"abstract":"<p><p>The proton motive force (PMF) across the inner mitochondrial membrane drives ATP synthesis. Biochemistry textbooks give a maximum yield of 30-32 ATP per glucose, but this is a theoretical ceiling, reached only under complete coupling with ATP synthase as the sole consumer of the gradient. No living cell operates there. The PMF is a shared resource, and its allocation among consumers sets the mitochondrion's effective output: the gap between theoretical and effective yield is a reallocation to transport, redox maintenance, and biogenesis. This review re-examines the textbook yield, including the c-ring stoichiometry of ATP synthase, and catalogs the major PMF consumers and their proton costs. The widely quoted figure corresponds to no measured or structurally determined stoichiometry, a mismatch noted previously and consolidated here, and the c-ring subunit count is an upper bound on synthase efficiency under ideal coupling. We assemble these costs into a consolidated proton budget: a range whose upper limit is the ceiling at which the PMF drives ATP synthesis alone. Its lower limit cannot yet be calculated, because the resting flux through most PMF consumers has never been measured; we therefore list every term that this calculation would require and mark those still missing. The result is a framework for reasoning, not a closed set of numbers. Practical consequence: the PMF and membrane potential are composite quantities, so a change in membrane potential should not be read as a change in ATP synthesis, nor the non-phosphorylating residual as passive leak.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149340338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Direct patch-clamp recording reveals TRPML2-dependent cation conductance across pathogen-containing vacuole membranes.","authors":"Hsuan-Ti Wang, Chieh-Hua Fu, Dennis Ko, Chi-Yuan Yao, Yu-Huan Tsai, Shu-Jung Chang, Cheng-Chang Chen","doi":"10.1152/ajpcell.90144.2026","DOIUrl":"https://doi.org/10.1152/ajpcell.90144.2026","url":null,"abstract":"<p><p>Transient receptor potential mucolipin 2 (TRPML2), a cation channel encoded by <i>MCOLN2</i> and localized to endolysosomal compartments, has been implicated in restricting <i>Salmonella enterica</i> replication through regulation of the Salmonella-containing vacuole (SCV). However, direct electrophysiological evidence of TRPML2 activity on the SCV membrane has been lacking. Using <i>S. enterica</i> serovar Typhi as a model, we optimized infection and patch-clamp conditions to directly access SCVs in infected THP-1 cells and record vacuolar ion currents. SCVs from wild-type cells exhibited robust inward currents at negative potentials that were reduced in TRPML2-knockout cells and enhanced by TRPML2 agonists. Under Mg²⁺-permeant conditions, SCVs displayed TRPML2-dependent Mg²⁺ conductance, supporting a role for TRPML2 in regulating Mg²⁺ availability during <i>S.</i> Typhi infection. Ca²⁺-permeant recordings further showed agonist-responsive inward currents on SCVs, indicating that SCV-localized TRPML2 retains broader divalent-cation conductance. Basal currents were also better maintained on SCVs than on bacteria-negative vacuoles isolated from uninfected bystander cells within the same cultures. PI3P reduced current rundown, suggesting that the phosphoinositide environment of SCVs may help sustain TRPML2 activity. Together, these findings provide the first direct electrophysiological characterization of a pathogen-containing vacuole and establish a tractable platform for investigating host ion-channel function at the host-pathogen interface.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149340339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Small Nucleolar RNAs, Big Impact: Biogenesis, Mechanisms, and Roles in Health and Disease.","authors":"Suriya Muthukumaran Natarajaseenivasan, Amit Kumar Rai, Nedjheda Pierre, Mikhael E Joseph, Minh Lam, Pawan Sharma, Venkata Naga Srikanth Garikipati","doi":"10.1152/ajpcell.90164.2026","DOIUrl":"https://doi.org/10.1152/ajpcell.90164.2026","url":null,"abstract":"<p><p>Non-coding RNAs (ncRNAs) are a diverse class of regulatory molecules classified by their size, localization, and function. Among them, small nucleolar RNAs (snoRNAs) are 60-300-nucleotide small non-coding RNAs that are primarily encoded within intronic regions of protein-coding or non-coding host genes. They are broadly categorized into three types: C/D box snoRNAs (SNORDs), H/ACA box snoRNAs (SNORAs), and Cajal body-specific RNAs (scaRNAs). SNORDs and SNORAs primarily mediate RNA modifications through 2'-O-methylation (Nm) and pseudouridylation (Ψ), respectively, whereas scaRNAs specialize in modifying small nuclear RNAs (snRNAs) within the Cajal body, which is crucial for splicing processes. Recent discoveries have broadened the functional landscape of snoRNAs beyond their canonical roles, uncovering non-canonical functions in protein secretion and the identification of snoRNA/scaRNA reads within glycoRNA-associated small RNA populations, suggesting novel mechanisms of cellular communication and pathophysiology. This review offers an integrative discussion of snoRNAs, focusing on their biogenesis, functions, developmental roles, and implications in various diseases, while providing detailed insights into these RNAs.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149317139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of TYK2 attenuates hyper IL-6- and Oncostatin M-mediated Calcium Signalling in Sensory Neurons.","authors":"Thomas Pritchard, Rohit Gupta, Kyara De Oliveira Taborda, James P Higham, Qasim Aziz, David C Bulmer","doi":"10.1152/ajpcell.90084.2026","DOIUrl":"https://doi.org/10.1152/ajpcell.90084.2026","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD) is characterised by chronic pain, a debilitating symptom for which effective treatments are few and far between. IBD pathogenesis includes the prevalence of a variety of pro-inflammatory cytokines, including the Interleukin-6 (IL-6) family members Il-6 and Oncostatin M (OSM). Previous research has shown disruption of OSM signaling can modulate nociceptor sensitization and activation, however the downstream signalling pathway is unknown. When an <i>in silico</i> analysis of murine colonic sensory neuronal populations was undertaken for receptor expression for OSM and other factors necessary for intracellular signaling, we can find diverse expression indicative of functional signaling. We were able to observe that hyper Il-6 (Il-6 bound to the soluble Il-6 receptor) and OSM can elicit activation of a subset of murine sensory neurons by finding an increase in calcium mobilization following superfusion. This could then be attenuated by the pharmacologic inhibition of all janus kinases or interestingly, TYK2 alone. Furthermore, inhibition of transient receptor potential vanilloid 1 or transient receptor potential ankyrin 1 ion channels, which are known to be sensitized by OSM in other sensory neurons, also reduced the proportion of OSM-responsive neurons. This further understanding of OSM signaling in sensory neurons creates avenues for more extensive research into the molecular mechanisms occurring as well as the potential to exploit these therapeutically to induce analgesia in a subset of neurons.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149317138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WNK463 stimulates K-Cl cotransport independently of WNK kinase activity.","authors":"Mohammed Z Ferdaus, Andrew S Terker, Liangping Li, Emily L Days, Joshua A Bauer, Eric Delpire","doi":"10.1152/ajpcell.90105.2026","DOIUrl":"10.1152/ajpcell.90105.2026","url":null,"abstract":"<p><p>K-Cl cotransport (KCC) mediates the Na⁺-independent, tightly coupled movement of K⁺ and Cl^- across biological membranes and is characteristically activated by cell swelling. Here, we show that swelling-activated KCC-mediated K⁺ influx is absent in eight transformed mammalian cell lines, including HEK293-T cells. Nevertheless, KCC function can be induced in all these cells by treatment with the with-no-lysine kinase (WNK) inhibitor WNK463. Activation of KCC-mediated K⁺ influx requires concentrations of WNK463 that are approximately two orders of magnitude higher than those needed to inhibit Na-K-2Cl cotransporter 1 (NKCC1). This marked difference suggests that the effect of WNK463 on KCC is not mediated by inhibition of WNK kinases themselves but rather through one or more alternative kinase targets. This conclusion is further supported by experiments performed in cells in which all four WNK kinase genes were disrupted. In these cells, WNK463 retained its ability to activate KCC, demonstrating that its effect is independent of WNK kinase expression. The WNK463 effect exhibits measurable activation and deactivation kinetics, with an activation time constant of approximately 18 minutes and an inactivation time constant of approximately 50 minutes. To identify the kinase(s) responsible for WNK463-induced activation of KCC, we screened a kinase inhibitor library containing approximately 1,100 compounds. Activation of KCC was PP121 sensitive and PI-103 insensitive, suggesting involvement of tyrosine kinases. Collectively, these results indicate that transformed mammalian cell lines possess a kinase-dependent mechanism that suppresses KCC activity. Both WNK463 and PP121 can relieve this suppression, but the responsible kinase appears to be distinct from WNK kinases and remains unidentified. Further studies will be required to define the signaling pathway that prevents K-Cl cotransport activity in these cells.<b>NEW & NOTEWORTHY</b> This study provides evidence that cells in culture that divide indefinitely and escape control of normal cellular growth (or \"transformed\" cells) fail to demonstrate swelling-activated K⁺ influx but exhibit the with-no-lysine kinase (WNK) inhibitor WNK463-induced K-Cl cotransport. As K-Cl cotransport activation by WNK463 still occurs in cells targeted for WNK kinase, the mechanism at play cannot be a WNK kinase. This work provides the framework and rationale for the discovery of a novel WNK463 target.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"331 5","pages":"C1406-C1419"},"PeriodicalIF":5.4,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149260559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Somatostatin and its type 2 receptor expression in the pregnant and laboring myometrium.","authors":"Oksana Shynlova, Adam Boros-Rausch, Anuradha Baishnob, Anna Dorogin, Eduardo Aguiar-Cabeza, Lubna Nadeem, Stephen J Lye","doi":"10.1152/ajpcell.00050.2026","DOIUrl":"10.1152/ajpcell.00050.2026","url":null,"abstract":"<p><p>Uterine contractility is regulated by the interaction of myogenic, neurogenic, and hormonal mechanisms. The hormonal peptide somatostatin (SST) is significantly increased in human plasma during late pregnancy and term labor (TL). SST mediates its effects by a family of G-protein-coupled receptors (SSTR1-5). Activation of somatostatin receptor type 2 (SSTR2) facilitates the contractility of smooth muscles, including the human gut and nonpregnant pig uterus. We hypothesized that SST/SSTR2 play a role in labor contractions, both term and preterm. The expression and localization of SST/SSTR2 were studied in human, rat, and mouse pregnant and laboring uterine tissues. Rodents' uteri were collected throughout gestation, TL, and preterm labor (PTL). Human myometrial biopsies were collected from TL and PTL women undergoing cesarean section. Human and rodent uterine tissues were fixed in formalin for immunohistochemistry (<i>n</i> = 4-7/group). Immunostaining of human and rodent' myometrium revealed stronger SSTR2 protein expression by myocytes and tissue macrophages during TL and PTL, as compared with not-in-labor patients or rodents. To examine the SST/SSTR2 mechanism, human monocytes were isolated from maternal peripheral blood and differentiated into macrophages. Primary human myocytes were isolated from the myometrium, cultured, and subjected to static mechanical stretch in vitro. Proteins were extracted and analyzed by immunoblotting, and the results indicate stretch-induced upregulation of SSTR2 in myocytes. Cell-conditioned media were analyzed by SST enzyme-linked immunosorbent assay (ELISA), indicating that human myocytes are a source of SST. When treated with exogenous SST, human myocytes induced contraction of a collagen gel. We conclude that SST/SSTR2 signaling may play a role in the process of labor in humans.<b>NEW & NOTEWORTHY</b> We show for the first time that somatostatin receptor type 2 (SSTR2) expression is upregulated in human and rodent myometrium during term and preterm labor. SSTR2 is expressed by myocytes and resident macrophages and is induced by mechanical stretch and inflammatory conditions. Human myocytes secrete somatostatin (SST), and its binding to SSTR2 enhances myocyte contractility in collagen gels, revealing a stretch- and inflammation-responsive SST-SSTR2 axis that promotes uterine contraction.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1145-C1161"},"PeriodicalIF":5.4,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148981870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of von Willebrand factor-enriched extracellular vesicles and their association with platelet adhesion in COVID-19.","authors":"Ling Chen, Aatish Mahajan, Anil Kumar Ram, Prabhakar Chalise, Quan Zhang, Huan Dong, Zhijian Wu, Liang Zheng, X Long Zheng, Leslie Spikes, Navneet Kaur Dhillon","doi":"10.1152/ajpcell.00374.2026","DOIUrl":"10.1152/ajpcell.00374.2026","url":null,"abstract":"<p><p>Microvascular thrombosis is a hallmark of severe COVID-19 and a major contributor to adverse clinical outcomes. Extracellular vesicles have emerged as key mediators of thromboinflammation, yet their functional and molecular characteristics remain incompletely understood. Here, we investigated the prothrombotic activity, cellular origin, and von Willebrand factor (VWF) composition of plasma-derived small extracellular vesicles (SEVs) from hospitalized patients with COVID-19. We demonstrate that SEVs from critically ill patients with COVID-19 markedly enhance platelet adhesion and thrombus formation under arterial shear conditions and promote endothelial activation, as evidenced by increased release of ICAM-1 and VCAM-1. These SEVs were highly enriched in ultra-large VWF multimers, with significantly elevated high-to-low molecular weight ratios compared with controls. Flow cytometric analysis showed increased circulating SEVs derived from leukocytes, platelets, and endothelial cells in severe disease, with VWF-positive SEVs predominantly originating from endothelial cells. The enrichment of VWF-SEVs was independent of gender and diabetes status, suggesting a primary association with disease severity. Collectively, these findings indicate that SEVs, particularly those rich in endothelial-derived VWF, are associated with platelet activation and may contribute to the prothrombotic milieu in COVID-19. These findings underscore the importance of VWF-positive SEVs as biomarkers of disease severity and warrant further investigation into their role in COVID-19-related vascular pathology.<b>NEW & NOTEWORTHY</b> Circulating small extracellular vesicles in patients with COVID-19 carrying ultra-large VWF multimers boost platelet adhesion and activate endothelial cells, highlighting a potential driver and biomarker of COVID-19-associated coagulopathy.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1555-C1563"},"PeriodicalIF":5.4,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13726893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149260541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Noninvading cells that coordinate with tip cells during angiogenic sprout initiation exhibit a molecular signature driven by YAP and TAZ.","authors":"Colette A Abbey, Solimar M Alvarez Cruz, Guillermo I Peralta, Tamara Natour, Ashley Coffell, Natalia Mejia, Akshaya Kannan, Sanjukta Chakraborty, Gregg B Wells, Carl A Gregory, Kayla J Bayless","doi":"10.1152/ajpcell.90147.2026","DOIUrl":"10.1152/ajpcell.90147.2026","url":null,"abstract":"<p><p>Angiogenesis requires endothelial cell (EC) plasticity and differentiation into either invasive, migratory tip cells or proliferative stalk cells. Using a transcriptional analysis that distinguished tip cells from noninvading (NON) cells in three-dimensions (3-D), we observed that approximately half of the significantly upregulated transcripts in the noninvading population were direct targets of Yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Although YAP and TAZ were reported to control the decision to divide versus differentiate in other cell types, a careful investigation of the actions of YAP and TAZ in ECs has not been performed in 3-D. Immunofluorescence confirmed that nuclear YAP and TAZ levels were elevated in noninvading versus tip cells. Noninvading cells also entered the cell cycle more readily than tip cells, and activation of YAP and TAZ increased S-phase entry and reduced cell invasion. Blockade of S-phase entry had no effect on invasion responses, indicating that driving cell division largely excluded sprouting, whereas blocking proliferation did not deter sprouting. Consistent with prior reports, silencing both YAP and TAZ reduced sprouting responses; however, individual silencing of YAP and TAZ revealed divergent functions. YAP silencing resulted in the formation of significantly longer filopodia, whereas silencing TAZ decreased invasion and shortened filopodia. Conversely, YAP overexpression reduced filopodia formation. Altogether, this study reveals that YAP and TAZ localize more frequently to the nucleus in noninvading cells but remain more cytoplasmic in tip cells, consistent with a proliferative phenotype in non-tip cells. These results provide insights into how endothelial plasticity is regulated during angiogenic sprout initiation in 3-D.<b>NEW & NOTEWORTHY</b> Transcriptional analysis of early three-dimensional (3-D) angiogenic sprout initiation revealed that the cells that do not initiate sprouting exhibited a unique gene signature, robustly expressing Yes-associated protein 1 (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) target genes. These cells exhibited higher nuclear YAP/TAZ and entered the cell cycle more readily than tip cells; YAP/TAZ activation also induced the noninvading (NON) phenotype. Finally, we uncovered divergent functions for YAP and TAZ in filopodia formation, gaining new insights into angiogenic sprout initiation and endothelial plasticity in 3-D.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1257-C1273"},"PeriodicalIF":5.4,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149056975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}