Katari Venkatesh

Aims: The transient receptor potential vanilloid 4 ion channel is widely expressed in the gastrointestinal tract and contributes to epithelial barrier regulation, mechanosensation and innate immune signaling. However, its role in shaping gut microbiota composition and intestinal metabolic homeostasis remains unclear. This study aimed to determine whether deletion of TRPV4 influences gut microbial composition and intestinal ammonia levels.Materials and Methods: Fecal microbiota from wild type and TRPV4 knockout mice were analyzed using taxonomic profiling and microbial diversity approaches. Alpha diversity and beta diversity metrics were used to evaluate microbial richness, evenness, phylogenetic diversity and community structure. Ammonia concentration and pH were measured in cecal and colonic contents.Key Findings: Phylogenetic diversity differed significantly between wild type and TRPV4 knockout mice whereas microbial richness and evenness were not altered. Beta diversity analysis revealed marked differences in microbial community composition between genotypes. The ratio of Bacillota to Bacteroidetes was reduced by approximately fifty percent in TRPV4 knockout mice due to decreased Bacillota and increased Bacteroidetes abundance. In addition, TRPV4 knockout mice exhibited significantly elevated ammonia levels in both the colon and cecum compared with wild type mice.Significance: Deletion of TRPV4 alters gut microbial community structure and intestinal nitrogen metabolism without affecting overall microbial richness or evenness. These findings identify TRPV4 as a novel regulator of gut microbiota composition and metabolic homeostasis and suggest that ion channel dependent signaling contributes to the regulation of gut microbial ecology and metabolite balance.

Angiogenesis, a cornerstone of vascular development, tissue regeneration, and tumor progression, is critically orchestrated by the metabolic behavior of endothelial cells (EC). Recent discoveries have redefined EC not as metabolically uniform entities, but as spatially and functionally heterogeneous populations whose metabolic states govern their angiogenic potential. This review presents a comprehensive synthesis of metabolic zonation in EC, spanning arterial, venous, and capillary domains, and highlights cell-type-specific programs during sprouting angiogenesis—including tip, stalk, and phalanx cells. We explore how distinct metabolic pathways—glycolysis, oxidative phosphorylation, fatty acid oxidation, and glutaminolysis—are differentially used across tissue contexts such as the brain, skeletal muscle, kidney, and tumor microenvironments. We discuss technological breakthroughs in spatial metabolomics, temporal (circadian) regulation of endothelial metabolism, and emerging clinical strategies to target EC metabolic vulnerabilities in cancer and ischemic diseases. Furthermore, we advocate for spatiotemporal modeling of EC metabolism using computational and machine learning frameworks to predict angiogenic behavior and accelerate therapeutic discovery. This integrative perspective underscores the need for precision-targeted angiogenic interventions and establishes metabolic zonation as a foundational principle in vascular biology.

Emerging evidence highlights the pivotal role of gut microbiota in regulating cardiovascular health and disease. The gut microbiota, a diverse community of microorganisms residing in the gastrointestinal tract, interacts with its host through metabolites, immune modulation, and systemic signaling pathways, collectively shaping cardiovascular physiology. Dysbiosis, or an imbalance in gut microbial composition, has been linked to various cardiovascular diseases (CVDs), including hypertension, heart failure and atherosclerosis. Key microbial metabolites such as short‐chain fatty acids (SCFAs), trimethylamine N‐oxide (TMAO) and lipopolysaccharides (LPS) have been implicated in mechanisms involving endothelial, cardiac fibroblast, cardiomyocyte dysfunction, systemic inflammation, and metabolic dysregulation. This review explores the dynamic interplay between the gut and the heart, focusing on: gut microbiota composition and its alterations in CVD; microbial‐derived metabolites and their mechanistic roles in cardiovascular pathophysiology; pathways linking gut dysbiosis to endothelial, cardiac fibroblast and cardiomyocyte dysfunction, inflammation, and immune responses; and therapeutic opportunities targeting the gut‐heart axis, including dietary interventions, prebiotics, probiotics and emerging microbiota‐based strategies. By unraveling these intricate relationships, we aim to provide a comprehensive understanding of how gut microbiota shape CVD pathophysiology and discuss potential avenues for novel therapeutics in precision medicine.

Bladder cancer (BLCA) is the second most common urologic cancer in the US and worldwide which mostly affects the aging population. Despite several ongoing clinical trials, treatment paradigms for BLCA have not changed significantly. Here, we investigated the expression of transient receptor potential vanilloid type 4 (TRPV4) in BLCA patients and its role in calcium influx, cell proliferation, and migration using normal human urothelial cells and BLCA cells. Bioinformatic analysis of the UALCAN and cBioPortal databases revealed that TRPV4 expression is significantly higher in human BLCA tissues compared to adjacent normal tissues. Further, the TRPV4 expression was markedly elevated in early-stage BLCA and upregulated in muscle-invasive bladder cancer (MIBC) tissues. TRPV4 is expressed in both normal urothelial (SV-HUC-1) and BLCA (T-24) cells and functional assays demonstrated enhanced TRPV4-mediated calcium influx in T-24 compared to SV-HUC-1 cells. T-24 cells exhibited higher spreading on extracellular matrix (ECM) gels with increasing stiffness (0.2, 8, and 50 kPa) and exhibited migratory phenotype compared to SV-HUC-1 cells. Pharmacological inhibition of TRPV4 significantly reduced proliferation and migration in T-24 cells but had minimal effects on normal cells. Finally, treatment with cisplatin significantly reduced TRPV4 protein levels and TRPV4-mediated calcium influx in chemosensitive UM-UC-3 cells, which remained unchanged in chemoresistant T-24 cells, suggesting a potential role of TRPV4 in chemoresistance. In conclusion, TRPV4 may contribute to bladder cancer progression by regulating cell proliferation and migration and may impart resistance to chemotherapy. Targeting TRPV4 could present a novel therapeutic approach for managing bladder cancer progression and overcoming chemoresistance. Significance Statement: This study identifies TRPV4 as a critical driver of BLCA progression. Elevated TRPV4 gene expression in both early-stage and muscle-invasive bladder cancer (MIBC) tissues is associated with increased calcium signaling, cell proliferation, and migration. Importantly, TRPV4 inhibition selectively reduces BLCA growth and motility. Furthermore, TRPV4 is downregulated by cisplatin in chemo-sensitive but not chemo-resistant BLCA cells, underscoring its key role in bladder cancer chemoresistance. These findings position TRPV4 as a therapeutic target for enhancing BLCA treatment and overcoming drug resistance.

Opioid receptors are G protein‐coupled receptors expressed by various cells in the heart, including myocytes and nerve fibres, and play a crucial role in modulating cardiac function. These receptors influence neural transmission, heart rate and myocyte contractility, offering cardioprotection. Our review provides a comprehensive examination of opioid receptor functions across multiple cardiovascular cell types, including cardiomyocytes, endothelial cells and smooth muscle cells, encompassing excitation–contraction coupling and vascular tone regulation. Additionally, we address the crosstalk between opioid receptors and other systems, such as the β‐adrenoceptor system and the renin–angiotensin system. This integrated approach enables a more complete understanding of how opioid systems influence overall cardiovascular homeostasis, presenting significant advances in the field. Understanding the role of these receptors could help in developing novel treatments for various cardiovascular conditions. In conclusion, this review discusses the importance of opioid receptors and their signalling pathways in mediating cardiovascular functions, highlighting their potential as therapeutic targets for cardiovascular diseases.

Cell Therapies for Spinal Cord Injury". Shang et al. provided a comprehensive analysis of the current research status of spinal cord injury using the stem cell therapy. The findings provide a foundation for future research and clinical translation efforts of stem cell therapy in SCI research field. Guo et al. provided a thorough bibliometric and visualized research hotspots and trend analysis of cell transplantation in traumatic SCI. Sadaf et al. demonstrated the potential applicability of nobiletin a polymethoxylated flavonoid with anti-oxidative and anti-inflammatory effects as a neuroprotectant against chemical-induced neurotoxicity. Winn et al. provided a proof-of-concept using induced-pluripotent stem cell derived neuroepithelial stem cells as potential therapeutics for SCI. Sintakova and Romanyuk and Rybachuk et al. provided a comprehensive reviews on therapeutic role of extracellular vesicles, microRNA, neural stem cells (NSCs) embedded-hydrogels towards SCI therapy respectively. Spinal cord injury (SCI) is a devastating disease resulting from traumatic or nontraumatic conditions. SCI results in a range of complications, depending on the severity and location of injury. The potential consequences include physical impairment, paralysis, bowel, bladder and sexual dysfunction (Venkatesh, Ghosh et al., 2019). The annual prevalence of traumatic SCI is around 54 cases per one million people, and 18,000 new SCI cases each year are being recorded in the United States. The estimated number of people with SCI is approximately ranging from 255,000 to 383,000 in United states, (National Spinal Cord Injury Statistical Center, University of Alabama at Birmingham, 2024). The average of affected person's age has increased from 29 years during the 1970s to 43 since 2015 About 78% of new SCI cases since 2015 belong to male category (Ding, Hu et al., 2022). Vehicle accidents are the most recent leading cause of SCI injury, followed by falls, acts of violence (primarily gunshot wounds) and sports/recreation activities are also relatively common causes. Therefore, SCI patients face significant financial and health burdens. The

BACKGROUND: Left ventricular hypertrophy is a bipolar response, starting as an adaptive response to the hemodynamic challenge, but over time develops maladaptive pathology partly due to microvascular rarefaction and impaired coronary angiogenesis. Despite the profound influence on cardiac function, the mechanotransduction mechanisms that regulate coronary angiogenesis, leading to heart failure, are not well known. METHODS: We subjected endothelial-specific knockout mice of mechanically activated ion channel, TRPV4 (transient receptor potential cation channel subfamily V member 4; TRPV4 ^ECKO ) to pressure overload via transverse aortic constriction and examined cardiac function, cardiomyocyte hypertrophy, cardiac fibrosis, and apoptosis. Further, we measured microvascular density and underlying TRPV4 mechanotransduction mechanisms using human microvascular endothelial cells, extracellular matrix gels of varying stiffness, unbiased RNA sequencing, small interfering RNA, Western blot, quantitative-PCR, and confocal immunofluorescence techniques. RESULTS: We demonstrate that endothelial-specific deletion of TRPV4 preserved cardiac function, cardiomyocyte structure, and reduced cardiac fibrosis compared with TRPV4 ^lox/lox mice, 28 days post–transverse aortic constriction. Interestingly, comprehensive RNA sequencing analysis revealed an upregulation of proangiogenic factors (VEGFα [vascular endothelial growth factor α], NOS3 [nitric oxide synthase 3], and FGF2 [fibroblast growth factor 2]) with concomitant increase in microvascular density in TRPV4 ^ECKO hearts after transverse aortic constriction compared with TRPV4 ^lox/lox . Further, an increased expression of VEGFR2 (vascular endothelial growth factor receptor 2) and activation of the YAP (yes-associated protein) pathway were observed in TRPV4 ^ECKO hearts. Mechanistically, we found that downregulation of TRPV4 in endothelial cells induced matrix stiffness–dependent activation of YAP and VEGFR2 via the Rho/Rho kinase/large tumor suppressor kinase pathway. CONCLUSIONS: Our results suggest that endothelial TRPV4 acts as a mechanical break for coronary angiogenesis, and uncoupling endothelial TRPV4 mechanotransduction attenuates pathological cardiac hypertrophy by enhancing coronary angiogenesis.

Prostaglandin E ₂ (PGE ₂ ) has been implicated in counteracting fibroblast differentiation by TGFβ1 during pulmonary fibrosis. However, the precise mechanism is not well understood. We show here that PGE ₂ via EP ₂ R and EP ₄ R inhibits the expression of mechanosensory molecules Lysyl Oxidase Like 2 (LOXL2), myocardin‐related transcription factor A (MRTF‐A), ECM proteins, plasminogen activation inhibitor 1 (PAI‐1), fibronectin (FN), α‐smooth muscle actin (α‐SMA), and redox sensor (nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4)) required for TGFβ1‐mediated fibroblast differentiation. We further demonstrate that PGE ₂ inhibits fibrotic signaling via Yes‐associated protein (YAP) but does so independently from its actions on SMAD phosphorylation and conserved cylindromatosis (CYLD; deubiquitinase) expression. Mechanistically, PGE ₂ phosphorylates/inactivates YAP downstream of EP ₂ R/Gαs and restrains its translocation to the nucleus, thus inhibiting its interaction with TEA domain family members (TEADs) and transcription of fibrotic genes. Importantly, pharmacological or siRNA‐mediated inhibition of YAP significantly downregulates TGFβ1‐mediated fibrotic gene expression and myofibroblast formation. Notably, YAP expression is upregulated in the lungs of D. farinae ‐treated wild type (WT) mice relative to saline‐treated WT mice. Our results unravel a unique role for PGE ₂ ‐YAP interactions in fibroblast differentiation, and that PGE ₂ /YAP inhibition can be used as a novel therapeutic target in the treatment of pathological conditions associated with myofibroblasts like asthma.

Fibrosis is an irreversible, debilitating condition marked by the excessive production of extracellular matrix and tissue scarring that eventually results in organ failure and disease. Differentiation of fibroblasts to hypersecretory myofibroblasts is the key event in fibrosis. Although both soluble and mechanical factors are implicated in fibroblast differentiation, much of the focus is on TGF-β signaling, but to date, there are no specific drugs available for the treatment of fibrosis. In this review, we describe the role for TRPV4 mechanotransduction in cardiac and lung fibrosis, and we propose TRPV4 as an alternative therapeutic target for fibrosis.