Biology subjects

Simpson, C. E.

Publications and source records attributed to Simpson, C. E..

3 recordsLinked to original sources

bioRxiv2026

Multicellular Programs Associated with Right Ventricular Adaptation in Pulmonary Arterial Hypertension

BackgroundRight ventricular (RV) adaptation determines outcomes in pulmonary arterial hypertension (PAH), yet multicellular molecular programs associated with adaptive versus maladaptive RV remodeling in living humans remain incompletely defined. MethodsWe collected 32 human RV tissue biopsies from patients with idiopathic PAH, systemic sclerosis-associated PAH (SSc-PAH), systemic sclerosis without pulmonary hypertension, with 24 nonfailing donor RVs serving as controls. We performed single-nucleus RNA sequencing and integrated cell-type specific transcriptional programs with contemporaneously obtained multi-beat pressure-volume loop measurements of RV contractility (Ees, end-systolic elastance) and RV-pulmonary arterial coupling (the ratio of Ees to Ea, the effective arterial load). SSc modification of PAH-associated biology was assessed using interaction terms. Bulk RV proteomic pathway enrichment was performed to assess an orthogonal molecular layer, and exploratory cell-cell communication analyses alongside independent spatial transcriptomic analyses were performed to contextualize key findings. ResultsPAH was associated with broad depletion of biosynthetic, trafficking, and mitochondrial programs across cell types. SSc modified the magnitude of many PAH-associated transcriptional programs while largely preserving pathway directionality. Significant multicellular pathway enrichments were associated with RV-pulmonary arterial coupling. Joint analysis of Ees, Ea, and Ees/Ea identified biologic programs associated with different RV responses to varying loading conditions. Preserved coupling was characterized by enriched extracellular matrix, laminin-integrin, receptor tyrosine kinase, mitochondrial, and translational programs involving fibroblast, endothelial, endocardial, and cardiomyocyte compartments. Cell- cell communication analyses predicted coordinated stromal-vascular signaling networks involving laminin-integrin and endothelial-to-mural signaling in preserved coupling. Proteomic and spatial analyses supported recurrent multicellular themes. ConclusionsRV adaptation in PAH is associated with distinct, coordinated multicellular programs that vary with load and contractile response. RV-PA coupling in PAH is associated with multicellular remodeling that extends beyond cardiomyocytes and reflects organized vascular-stromal support architecture. These findings identify extracellular matrix, laminin- integrin signaling, mitochondrial, and translational programs as associated with adaptive RV remodeling in PAH. Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LICell type-resolved molecular profiling of living human RV tissue identifies PAH-associated depletion of biosynthetic, trafficking, mitochondrial, and repair-associated programs across multiple cardiac cell types. C_LIO_LIIntegration with contemporaneously obtained pressure-volume loop physiology demonstrates that preserved RV-pulmonary arterial coupling under lower load was associated predominantly with cardiomyocyte mitochondrial and metabolic competency, whereas preserved coupling under higher load was associated with extracellular matrix remodeling and vascular-stromal signaling. C_LIO_LIProteomic, cell-cell communication, and spatial analyses provided orthogonal support for coordinated extracellular matrix and vascular-stromal programs associated with preserved RV-pulmonary arterial coupling. C_LI What are the clinical implications?O_LIThese findings shift the biology of RV adaptation from a predominantly cardiomyocyte- centered model toward a multicellular tissue model in which metabolic, matrix, and vascular support programs vary according to loading conditions and contractile states. C_LIO_LIExtracellular matrix-integrin signaling, endothelial-mural communication, and mitochondrial competency represent candidate pathways for mechanistic investigation toward RV-directed therapies in PAH. C_LI

molecular biology↗

bioRxiv2026

Metabolomic Network Analysis Reveals Reorganization of Lipid and Steroid Programs Linked to Right Ventricular-Pulmonary Vascular Function in Pulmonary Hypertension

BackgroundPulmonary arterial hypertension (PAH) is characterized by circulating metabolic alterations, but whether these reflect disease-specific metabolic programs or reorganization of normal metabolic architecture, and how they relate to right ventricular-pulmonary vascular function (RV-PV), remains unclear. We hypothesized that the PAH metabolome is organized into biologically coherent, co-regulated metabolic modules whose relationships to RV-PV function would provide insight into known and novel metabolic pathways. MethodsWe applied weighted gene co-expression network analysis (WGCNA) to untargeted metabolomic data from 412 PAH patients enrolled in the multicenter PVDOMICS study. Module preservation analysis was performed in 85 healthy controls, with external replication in an independent single-center pulmonary hypertension cohort of 89 patients. ResultsWGCNA identified 16 distinct metabolic modules organized around biologically coherent programs. A coherent fatty acid axis, spanning substrate pools, {beta}-oxidation intermediates, and conjugated fatty acid disposal products, formed a central organizing structure, with downstream fatty acid oxidation modules strongly associated with adverse hemodynamics and worse RV-pulmonary artery (PA) coupling. Acylcholine-enriched and 5-reduced androgen metabolite modules were associated with favorable hemodynamic indices. Module architecture was largely preserved in healthy controls, with subtle disease-associated modular reorganization, rather than emergence of novel modules, observed in PAH. Core modules were recovered in the replication cohort with conserved hub metabolites. ConclusionsThese findings establish a systems-level framework demonstrating that PAH involves structured intensification and reorganization of interconnected metabolic programs associated with favorable and adverse RV-PV phenotypes. This work provides new insight into the metabolic architecture underlying PAH and identifies coordinated metabolic pathways linked to pulmonary vascular and right ventricular function.

physiology↗

bioRxiv2024

Single-cell transcriptomics reveal diverging pathobiology and opportunities for precision targeting in scleroderma-associated versus idiopathic pulmonary arterial hypertension

IntroductionPulmonary arterial hypertension (PAH) involves progressive cellular and molecular change within the pulmonary vasculature, leading to increased vascular resistance. Current therapies targeting nitric oxide (NO), endothelin, and prostacyclin pathways yield variable treatment responses. Patients with systemic sclerosis-associated PAH (SSc-PAH) often experience worse outcomes than those with idiopathic PAH (IPAH). MethodsLung tissue samples from four SSc-PAH, four IPAH, and four failed donor specimens were obtained from the Pulmonary Hypertension Breakthrough Initiative (PHBI) lung tissue bank. Single-cell RNA sequencing (scRNAseq) was performed using the 10X Genomics Chromium Flex platform. Data normalization, clustering, and differential expression analysis were conducted using Seurat. Additional analyses included gene set enrichment analysis (GSEA), transcription factor activity analysis, and ligand-receptor signaling. Pharmacotranscriptomic screening was performed using the Connectivity Map. ResultsSSc-PAH samples showed a higher proportion of fibroblasts and dendritic cells/macrophages compared to IPAH and donor samples. GSEA revealed enriched pathways related to epithelial-to-mesenchymal transition (EMT), apoptosis, and vascular remodeling in SSc-PAH samples. There was pronounced differential gene expression across diverse pulmonary vascular cell types and in various epithelial cell types in both IPAH and SSc-PAH, with epithelial to endothelial cell signaling observed. Macrophage to endothelial cell signaling was particularly pronounced in SSc-PAH. Pharmacotranscriptomic screening identified TIE2, GSK-3, and PKC inhibitors, among other compounds, as potential drug candidates for reversing SSc-PAH gene expression signatures. DiscussionOverlapping and distinct gene expression patterns exist in SSc-PAH versus IPAH, with significant molecular differences suggesting unique pathogenic mechanisms in SSc-PAH. These findings highlight the potential for precision-targeted therapies to improve SSc-PAH patient outcomes. Future studies should validate these targets clinically and explore their therapeutic efficacy.

bioinformatics↗