Biology subjects

Smith, L.

Publications and source records attributed to Smith, L..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Navigating parasite antigen genetic diversity in the design of Plasmodium vivax serological exposure markers for malaria

BackgroundPlasmodium vivax poses a major obstacle to malaria elimination because it can lie dormant in the liver for weeks or months before reactivating and causing a relapse of infection. These dormant forms (hypnozoites) cannot be detected using standard diagnostics, but recent P. vivax exposure and by proxy, hypnozoite carriage, can be inferred using antibody-based tests (serological markers). In this study, we examined how genetic variation in P. vivax affects the utility of these antibody markers, and whether redesigned antigens could improve performance. MethodsWe analysed global P. vivax genetic data to assess variation in leading serological markers. Based on this, we produced new antigen versions (haplotypes) that better reflect global sequence diversity, compared to the commonly used reference strain (Sal-1). Antibody responses against these new constructs were then tested using samples from well-characterised cohorts in Brazil and Thailand. Antibody levels were assessed in relation to how recently participants had a qPCR-detectable blood-stage P. vivax infection. We compared the ability of the haplotypes and reference constructs to correctly identify individuals infected within the prior 9-months. FindingsExtensive genetic diversity was identified in two P. vivax antigens, DBPII and MSP5. Several antigens had large numbers of circulating haplotypes globally, with the percentage with similar sequence identity to the reference Sal-1 ranging from 0.4% (MSP5) to 99% (S16). Two antigens exhibited strong differences in immunogenicity by region and construct (RBP2a and DBPII). However, for most proteins (5 out of 8), these differences had little impact on the accuracy of identifying recent exposure. In cases where performance was affected (e.g. RBP2a), this could be overcome by adding multiple antigens into the classification model. InterpretationEven highly diverse antigens can be effective serological exposure markers. Our findings highlight the importance of testing the impact of genetic diversity when designing serological tests and suggest practical strategies, such as using a mix of antigens, to ensure consistent performance across regions.

microbiology↗

bioRxiv2025

Functional genomics and tumor microenvironment analysis reveal prognostic biological subtypes in Mantle cell lymphoma

Mantle cell lymphoma (MCL) is a genetically and clinically heterogeneous B-cell malignancy. We studied two MCL cohorts with differing treatment patterns: one enriched for immunochemotherapy, the other for chemotherapy alone. TP53 alterations were consistently associated with poor prognosis, whereas ATM mutations correlated with improved outcomes following rituximab-based chemotherapy. Based on recurrent genetic events, six clusters were identified and refined into three prognostic groups: high-risk (TP53 mutations and deletions at 17p13.3, 13q14.2, and 19p13.3), intermediate-risk (ATM and epigenetic regulator mutations, or gains at 8q/17q/15q), and low-risk (lacking TP53 alterations, rare ATM mutations without 11q deletions, gains at 3q, deletions at 6q). Transcriptomic analysis revealed enrichment of proliferation, metabolism-promoting gene signatures in high-risk; angiogenesis and NOTCH signaling in intermediate-risk; and proinflammatory-related (i.e., IFN, TNF) in low-risk MCLs. Multi-proteomic spatial profiling using imaging mass cytometry (IMC) demonstrated enrichment of CD8 T cells with high expression of exhaustion markers and dominant population of myeloid cells skewed toward an M2-like phenotype. Compared to ATM-perturbed tumors, TP53-perturbed tumors exhibited enriched SOX11 tumor cells and enhanced tumor-immune cell interactions. Functional analysis revealed that p53 represses BCR signaling through PTPN6 activation. Collectively, these findings highlight distinct molecular and immune landscapes and reveal therapeutic vulnerabilities in high-risk TP53-altered MCL.

cancer biology↗

bioRxiv2025

SBMLNetwork: a framework for standards-based visualization of biochemical models

SBMLNetwork is an open-source software library that makes the SBML Layout and Render packages practical for standards-based visualization of biochemical models. Current tools often manage model visualization data in custom-designed, tool-specific formats and store it separately from the model itself, hindering interoperability, reproducibility, and the seamless integration of visualization with model data. SBMLNetwork addresses these limitations by building directly on the SBML Layout and Render specifications, automating the generation of standards-compliant visualization data, offering a modular implementation with broad integration support, and providing a robust API tailored to the needs of systems biology researchers. We illustrate the capabilities of SBMLNetwork across key visualization tasks, including SBGN-compliant visualization, application of predefined style templates, layout arrangement to reflect pathway logic, and integration of model data into network diagrams. These examples demonstrate how SBMLNetwork enables high-level visualization features and seamlessly translate user intent into reproducible outputs that support both structural representation and dynamic data visualization within the SBML model. SBMLNetwork is freely available at https://github.com/sys-bio/SBMLNetwork under the MIT license.

systems biology↗

bioRxiv2025

Characterization of the functional and clinical impacts of CACNA1A missense variants found in neurodevelopmental disorders

CACNA1A encodes the P/Q-type CaV2.1 calcium channels whose function underlies neuronal excitability, presynaptic neurotransmitter release, and Ca2+ signaling in neurons. Pathogenic variants in CACNA1A have been found in individuals with various neurological conditions, including hemiplegic migraine, epilepsy, developmental delay, and ataxia. Clinical presentations can vary significantly between patients, with limited information known about the underlying neurobiology of these different clinical patterns. Adding further complication, prior work on pathogenic missense variants has demonstrated variable impacts on CaV2.1 channel function, sometimes in opposite directions. As such, the relationships between specific coding variants, electrophysiological properties, and clinical phenotypes remain elusive. In this study, we determined the biophysical properties of an allelic series of 42 de novo missense CACNA1A variants discovered in a neurodevelopmental disorder cohort of more than 31,000 individuals, together with the most common eight coding variants found in the general population. We found that all but one de novo variant altered at least one aspect of the channel properties examined, and the majority (70%) of the variants reduced the channel current density. In addition, for variants that encode human CaV2.1 channels (hCaV2.1) with detectable currents, nearly 50% altered how channels respond to membrane potential, while common variations did not significantly change any channel biophysical properties. Coupled with our functional analyses and AlphaMissense prediction, we showed that CaV2.1 missense variants significantly underlie the risk of developmental epileptic encephalopathy. Subsequently, we examined the physiological impact of variant hCaV2.1 using NEURON simulations as an omnibus output of neuronal function and found that abnormal biophysical channel properties have a profound impact on Purkinje cell excitability. Most interestingly, we correlated the clinical phenotype with molecular consequences of missense variants provided by our comprehensive functional analyses and found that distinct CaV2.1 channel molecular function is significantly associated with different clinical outcomes. By analyzing an entire allelic series of CACNA1A de novo changes in a large cohort of individuals with neurodevelopmental disorders, we provide a powerful approach to dissecting the role of missense variants in CACNA1A channelopathy, which in turn may help pave the way for future precision medicine initiatives.

neuroscience↗

bioRxiv2025

Development and validation of five native Aotearoa New Zealand genera-specific large brown macroalgal eDNA ddPCR assays

Environmental DNA is a rapidly growing methodology for ecological studies, leading to an increase in innovative techniques, such as the droplet-digital PCR (ddPCR), that can quantify and target DNA at a high rate of sensitivity for eDNA studies. Large brown macroalgae, Phaeophyceae, are an ecologically significant, diverse, and abundant benthic group in temperate-reef coastal environments. Members of Phaeophyceae, such as Laminariales and Fucales, are becoming recognized as potential significant contributors to Blue Carbon, although measurement of their contribution is challenging. The goal of the present study was to track the fate of specific large, brown macroalgae (kelp) genera detritus, by designing and validating five assays targeting the eDNA of kelp genera that are abundant in the coastal environments of Aotearoa New Zealand: Carpophyllum, Cystophora, Ecklonia, Lessonia, and Macrocystis. Short, diagnostic sequences of the mitochondrial cytochrome c oxidase subunit III gene (cox3) were targeted using ddPCR analysis. Specificity and sensitivity testing were conducted to validate the design of each assay for future use. All five assays produced no cross-amplification and had limits of detection (LoD) that were less than 1 copy/{micro}l. These novel, highly sensitive assays will be beneficial for future experimental and in situ eDNA studies that focus on any of these indigenous genera.

molecular biology↗

bioRxiv2025

Phenotypic analysis of 11,125 trio exomes in neurodevelopmental disorders

Genomic sequencing is widely used to identify causative genetic changes in neurodevelopmental disorders, such as autism, intellectual disability, and epilepsy. Most neurodevelopmental disorders also present with diverse clinical features, and delineating the interaction between causative genetic changes and phenotypic features is a key prerequisite for developing personalized therapies. However, assessing clinical features at a scale that parallels genomic sequencing remains challenging. Here, we standardize phenotypic information across 11,125 patient-parent trios with exome sequencing data using biomedical ontologies, analyzing 674,767 phenotypic terms. We find that individuals with de novo variants in 69 out of 261 neurodevelopmental genes exhibit statistically significant clinical similarities with distinct phenotypic fingerprints. We also observe that phenotypic relatedness follows a gradient, spanning from highly similar to dissimilar phenotypes, with intra-gene similarities suggesting clinically distinct subgroups for seven neurodevelopmental genes. For most genetic etiologies, only a small subset of highly phenotypically similar individuals carried de novo variants in the same gene, highlighting the heterogeneous and complex clinical landscape of neurodevelopmental disorders. Our study provides a large-scale overview of the dynamic relationship between genotypes and phenotypes in neurodevelopmental disorders, underscoring how the inherent complexity of these conditions can be deciphered through approaches that integrate genomic and phenotypic data.

genetics↗

bioRxiv2025

The influence of common testing floor surfaces on force plate data: implications for standardisation

Force plate testing is commonly used to assess athlete performance, however there is no research into the effect the surface underneath the force plate has on derived variables. The aim of this study was to investigate whether different surfaces underneath a force plate would elicit differences in derived force plate variables using a mechanical testing device. A mechanical testing device was used to assess force reduction, peak force, rate of force development (RFD) and contact time across seven common testing surfaces: vinyl, rubber, Olympic lifting platform, ground (CarpetF) and first floor (CarpetF) carpet, Mondo track and a sprung gymnasium floor (Sprung). Significant differences in force reduction, peak force, RFD, and contact time were found between flooring conditions (p < 0.05), with large to extremely large effect sizes. Sprung flooring exhibited the highest force reduction and lowest peak forces, while CarpetF demonstrated the lowest RFD and longest contact time. These findings highlight the flooring surface underneath the force plate during testing significantly influenced derived variables. Practitioners should exert caution and consideration to force plate testing location and advocate standardisation in flooring surface in order to ensure consistent and accurate results.

scientific communication and education↗

bioRxiv2025

NAMPT activity plays a key role in driving autoimmune processes that characterize type 1 diabetes development in mice

Type 1 diabetes (T1D) is characterised by destruction of pancreatic beta cells by islet-infiltrating cytotoxic lymphocytes, and elevated intra-islet secretion of pro-inflammatory cytokines. However, the underlying pathophysiological mechanisms remain incompletely understood. We hypothesised that abnormal elevation of islet NAD, via activation of NAMPT, plays a key role in driving islet autoimmune processes in T1D. Here, we report that NAMPT inhibition protects against pro-inflammatory cytokine (IL-1{beta}, TNF and IFN{gamma}) mediated beta-cell dysfunction and apoptosis in isolated mouse and human islets. RNAseq revealed that NAMPT inhibition blocked cytokine-mediated gene expression linked to pro-inflammatory responses and leukocyte migration. In vivo, diabetes was induced in CD1 mice via multiple low dose streptozotocin (MLDS) injection. MLDS mice were administered the NAMPT inhibitor FK866 (10 mg/kg; IP) or saline equivalent for 16 days. These experiments demonstrated that NAMPT inhibition improved glycaemic control and beta-cell function and insulin content in MLDS mice. FK866 also reduced proportions of islet-residing TNF-producing CD4+T-cells and F4/80+macrophages, proliferation of spleen-derived CD4+ and CD8+T-cells, and proliferation of islet-derived CD4+T-cells and F4/80+macrophages. Finally, we report that NAMPT inhibition was able to block pro-inflammatory cytokine-mediated migration of cytotoxic CD8+T-cells into isolated islets, using an in vitro transwell platform. This data supports a key immunomodulatory role for NAMPT in islet autoimmunity. NAMPT inhibition may represent a novel therapeutic approach for T1D. The effects of increased NAD levels on islet inflammation require in-depth characterisation, and caution should be exercised with regard to use of NAD boosting supplements, particularly in individuals at risk of developing T1D.

cell biology↗

bioRxiv2024

Occurrence of Aneuploidy Across the Range of Coast Redwood (Sequoia sempervirens)

1Aneuploidy, a condition characterized by an abnormal number of chromosomes, can have significant consequences for fitness of an organism, often manifesting in reduced fertility and other developmental challenges. In plants, aneuploidy is particularly complex to study, especially in polyploid species such as coast redwood (Sequoia sempervirens), which is a hexaploid conifer (2n=6x=66). This study leverages a novel Markov Chain Monte Carlo (MCMC) method based on sequence depth to investigate the occurrence of aneuploidy across the range of coast redwood. We show that aneuploidy is prevalent in second-growth redwoods, predominantly as additional chromosomes, while tissue culture plants frequently experience chromosome loss. Although our study does not directly assess the fitness of aneuploids, the frequency of chromosomal instability observed in tissue culture plants compared to second-growth and old-growth trees raises questions about their long-term developmental viability and potential to become established trees. These findings have significant implications for redwood conservation and restoration strategies, especially as tissue culture becomes the primary mode of producing nursery stock plants used in reforestation.

plant biology↗

bioRxiv2024

A Single Chimeric Spike Antigen Induces Pan-Sarbecovirus Immunity

Next-generation vaccines are required to address the evolving nature of SARS-CoV-2 and to protect against emerging pandemic threats from other coronaviruses. These vaccines should aim to elicit broad-protection, provide long-lasting immunity and facilitate equitable access for all populations. In this study, a panel of chimeric, full-length spike antigens were developed that incorporate mutations from previous, circulating and predicted SARS-CoV-2 variants. The lead candidate (CoVEXS5) was obtained from a high-yield production process in stable CHO cells with purity of >95%, long-term stability and elicitation of broadly cross-reactive neutralising antibodies when delivered to mice in a squalene emulsion adjuvant (Sepivac SWE). In both mice and hamsters, CoVEXS5 immunisation reduced clinical disease signs, lung inflammation and organ viral titres after SARS-CoV-2 infection, including challenge with the highly immunoevasive Omicron XBB.1.5 subvariant. In mice previously primed with a licenced protein vaccine (NVX-CoV2373), CoVEXS5 could boost T cell immunity, as well as neutralising antibodies levels against viruses from three sarbecoviruses clades. The breadth of sarbecovirus cross-reactivity elicited by CoVEXS5 exceeded that observed after boosting with the NVX-CoV2373 vaccine. These findings highlight the potential of a chimeric spike antigen, formulated in an open-access adjuvant, as a next-generation vaccine candidate to enhance cross-protection against emerging sarbecoviruses in vaccinated populations globally.

immunology↗

bioRxiv2024

Optimisation of a multiplexed, high throughput assay to measure neutralising antibodies against SARS-CoV-2 variants.

A multiplexed, lentivirus-based pseudovirus neutralisation assay (pVNT) was developed for high-throughput measurement of neutralising antibodies (nAbs) against three distinct SARS-CoV-2 spike variants. Intra-assay variability was minimised by optimising the plate layout and determining an optimal percentage transduction for the pseudovirus inoculum. Comparison of monoclonal antibody EC50 titres between single and multiplexed pVNT assays showed no significant differences, indicating reliability of the multiplexed assay. Evaluation of convalescent human sera confirmed assay validity, with consistent fold drops in EC50 for variant pseudoviruses relative to the ancestral strain observed across single and multiplexed assays. This multiplexed pVNT provides a reliable tool for assessing nAb responses against SARS-CoV-2 variants and could be used to accelerate preclinical vaccine assessment in preparation for the next coronavirus pandemic.

immunology↗

bioRxiv2024

SGLT2 inhibitors activate pantothenate kinase in the human heart

Inhibitors of sodium glucose cotransporter-2 (SGLT2i) demonstrate strong symptomatic and mortality benefits in the treatment of heart failure but appear to do so independently of SGLT2. The relevant pharmacologic target of SGLT2i remains unclear. We show here that SGLT2i directly activate pantothenate kinase 1 (PANK1), the rate-limiting enzyme that initiates the conversion of pantothenate (vitamin B5) to coenzyme-A (CoA), an obligate co-factor for all major pathways of fuel use in the heart. Using stable-isotope infusion studies, we show that SGLT2i promote pantothenate consumption, activate CoA synthesis, rescue decreased levels of CoA in human failing hearts, and broadly stimulate fuel use in ex vivo perfused human cardiac blocks from patients with heart failure. Furthermore, we show that SGLT2i bind to PANK1 directly at physiological concentrations and promote PANK1 enzymatic activity in assays with purified components. Novel in silico dynamic modeling identified the site of SGLT2i binding on PANK1 and indicated a mechanism of activation involving prevention of allosteric inhibition of PANK1 by acyl-CoA species. Finally, we show that inhibition of PANK1 prevents SGLT2i-mediated increased contractility of isolated adult human cardiomyocytes. In summary, we demonstrate robust and specific off-target activation of PANK1 by SGLT2i, promoting CoA synthesis and efficient fuel use in human hearts, providing a likely explanation for the remarkable clinical benefits of SGLT2i.

biochemistry↗

bioRxiv2024

Phylogenomics of the North American Desert Radiation Linanthus (Polemoniaceae) Reveals Mixed Trait Lability and No Single Geographic Mode of Speciation

PremiseUnderstanding how arid-adapted plants have diversified in harsh environments is a central question in evolutionary biology. Linanthus (Polemoniaceae) occurs in biodiverse dry areas of Western North America and exhibits extensive floral trait variation, multiple color polymorphisms, differences in blooming time, and variation in life history strategies. Here, we reconstruct the evolutionary history of this group. MethodsWe generated restriction-site associated (ddRAD) sequences for 180 individuals and target capture (TC) sequences for 63 individuals, with complete species sampling. Using maximum likelihood and pseudo-coalescent approaches, we inferred phylogenies of Linanthus and used these phylogenies to model the evolution of phenotypic traits and investigate the geographic speciation history of this genus. Key resultsShallow relationships are consistent and well supported with both ddRAD and TC data. Most species are monophyletic despite rampant local sympatry and range overlap, suggesting strong isolating barriers. The non-monophyly of some species is possibly due to rapid speciation or issues with current species delimitation. Perenniality likely evolved from annuality, a rare shift in angiosperms. Night blooming evolved three times independently. Flower color polymorphism is an evolutionarily labile trait and is likely ancestral. No single geographic mode of speciation characterizes the radiation but most species overlap in range, suggesting they evolved in parapatry. ConclusionsOur results illustrate the complexity of phylogenetic inference for recent radiations, even with multiple sources of genomic data and extensive sampling. This analysis provides a foundation to understand aridity adaptations, such as evolution of flower color polymorphisms, night blooming, and perenniality, as well as speciation mechanisms.

evolutionary biology↗

bioRxiv2024

A Rigorous Multi-Laboratory Study of Known PDAC Biomarkers Identifies Increased Sensitivity and Specificity Over CA19-9 Alone

A blood test that enables surveillance for early-stage pancreatic ductal adenocarcinoma (PDAC) is an urgent need. Independent laboratories have reported PDAC biomarkers that could improve biomarker performance over CA19-9 alone, but the performance of the previously reported biomarkers in combination is not known. Therefore, we conducted a coordinated case/control study across multiple laboratories using common sets of blinded training and validation samples (132 and 295 plasma samples, respectively) from PDAC patients and non-PDAC control subjects representing conditions under which surveillance occurs. We analyzed the training set to identify candidate biomarker combination panels using biomarkers across laboratories, and we applied the fixed panels to the validation set. The panels identified in the training set, CA19-9 with CA199.STRA, LRG1, TIMP-1, TGM2, THSP2, ANG, and MUC16.STRA, achieved consistent performance in the validation set. The panel of CA19-9 with the glycan biomarker CA199.STRA improved sensitivity from 0.44 with 0.98 specificity for CA19-9 alone to 0.71 with 0.98 specificity (p < 0.001, 1000-fold bootstrap). Similarly, CA19-9 combined with the protein biomarker LRG1 and CA199.STRA improved specificity from 0.16 with 0.94 sensitivity for CA19-9 to 0.65 with 0.89 sensitivity (p < 0.001, 1000-fold bootstrap). We further validated significantly improved performance using biomarker panels that did not include CA19-9. This study establishes the effectiveness of a coordinated study of previously discovered biomarkers and identified panels of those biomarkers that significantly increased the sensitivity and specificity of early-stage PDAC detection in a rigorous validation trial.

cancer biology↗

bioRxiv2024

Signal integration and integral feedback control with biochemical reaction networks

Biochemical reaction networks perform a variety of signal processing functions, one of which is computing the integrals of signal values. This is often used in integral feedback control, where it enables a systems output to respond to changing inputs, but to then return exactly back to some pre-determined setpoint value afterward. To gain a deeper understanding of how biochemical networks are able to both integrate signals and perform integral feedback control, we investigated these abilities for several simple reaction networks. We found imperfect overlap between these categories, with some networks able to perform both tasks, some able to perform integration but not integral feedback control, and some the other way around. Nevertheless, networks that could either integrate or perform integral feedback control shared key elements. In particular, they included a chemical species that was neutrally stable in the open loop system (no feedback), meaning that this species does not have a unique stable steady-state concentration. Neutral stability could arise from zeroth order decay reactions, binding to a partner that was produced at a constant rate (which occurs in antithetic control), or through a long chain of covalent cycles. Mathematically, it arose from rate equations for the reaction network that were underdetermined when evaluated at steady-state.

systems biology↗

bioRxiv2024

Curating models from BioModels: Developing a workflow for creating OMEX files

The reproducibility of computational biology models can be greatly facilitated by widely adopted standards and public repositories. We examined 50 models from the BioModels Database and attempted to validate the original curation and correct some of them if necessary. For each model, we reproduced these published results using Tellurium. Once reproduced we manually created a new set of files, with the model information stored by the Systems Biology Markup Language (SBML), and simulation instructions stored by the Simulation Experiment Description Markup Language (SED-ML), and everything included in an Open Modeling EXchange (OMEX) file, which could be used with a variety of simulators to reproduce the same results. On the one hand, the reproducibility procedure of 50 models developed a manual workflow that we would use to build an automatic platform to help users more easily curate and verify models in the future. On the other hand, these exercises allowed us to find the limitations and possible enhancement of the current curation and tooling to verify and curate models.

systems biology↗

bioRxiv2023

Action history and target uncertainty co-determine human reaching direction under time pressure

Given the inaccuracies that are inherent in biological sensory and motor functions, animal sensorimotor control should be probabilistic. Effective neural control systems for movement must estimate the most likely true state of the world on the basis of uncertain sensory information, and to select and execute movements that are most likely to be successful given motor variability. Bayesian inference dictates that if sensory information is ambiguous (e.g. low light conditions), animals should rely more on their past experience of target locations to guide motor planning, and less on their current sensory information about target location. Here we investigated how time pressure affects degree to which the precision of sensory information about a target influences movement direction bias towards previous target locations. We used a paradigm developed by Dekleva et al. (2016) that involved uncertain cues to the location of a hidden target for reaching with movement preparation time strictly controlled. One group of participants (n=10) were required to initiate their reaches within 150-300ms of target presentation, and a second group (n=10) were required to initiate their reaches with 1150-1300ms of target presentation. We found that participants relied more on prior target location information when target precision was reduced under time pressure, which suggests that integration of target uncertainty information according to Bayesian principles is an inherent component of sensorimotor transformation and does not require time-consuming cognitive processes.

neuroscience↗

bioRxiv2023

Targeting LOXL2 Improves Arterial Stiffness and Function in Angiotensin II-induced Hypertension in Males but not Females

BackgroundHypertension, a disease with known sexual dimorphism, accelerates aging associated arterial stiffening, in part due to the activation of matrix remodeling caused by increased biomechanical load. In this study, we tested the effect of biological sex and the role of the matrix remodeling enzyme lysyl oxidase like 2 (LOXL2) in hypertension induced arterial stiffening. MethodsAngiotensin II (Ang II) was delivered using osmotic pumps in Loxl2+/- and WT male and female mice. Blood pressure and pulse wave velocity (PWV) were measured noninvasively to assess hypertension and aortic stiffness. Wire myography and uniaxial tensile testing were used to test aortic vasoreactivity and mechanical properties. Aortic wall composition was examined by histology and Western blotting. The effect of biomechanical strain on LOXL2 expression and secretion by vascular smooth muscle (VSMC) and endothelial cells (EC) was evaluated by uniaxial cyclic stretching of cultured cells. The role of LOXL2s catalytic function on VSMC alignment in response to mechanical loading was determined with LOXL2 inhibition and knockout. ResultsAng II infusion induced hypertension in WT and Loxl2+/- mice of both sexes and increased PWV in WT males but not in Loxl2+/- males, WT females, or Loxl2+/- females. LOXL2 depletion protected males from Ang II mediated potentiation of vasoconstriction but worsened in females and improved aortic mechanical properties in both sexes. Histological analysis showed increased aortic wall thickness in hypertensive WT males but not females and increased intralamellar distance in both sexes, that was ameliorated in Loxl2+/- mice. Western blotting revealed increased collagen I, decreased collagen IV, and increased LOXL2 accumulation and processing in hypertensive mice. Hypertensive cyclic strain contributed to LOXL2 upregulation in the cell-derived matrix in VSMCs but not ECs. LOXL2s catalytic function facilitated VSMC alignment in response to biomechanical strain. ConclusionsIn males, arterial stiffening in hypertension is driven both by VSMC response and matrix remodeling. Females exhibit a delayed onset of Ang II-induced hypertension with minimal ECM remodeling but with VSMC dysfunction. LOXL2 depletion ameliorates arterial stiffening and preserves functional contractility and aortic structure in male hypertensive mice. LOXL2 depletion improves aortic mechanics but worsens aortic contractility in hypertensive females. VSMCs are the primary source of LOXL2 in the aorta and hypertension increases LOXL2 processing and shifts to collagen I accumulation. Overall, LOXL2 depletion offers protection in young hypertensive males and females.

physiology↗