👤 Andreas Edsfeldt

Atherosclerotic plaques are the leading cause of cardiovascular events. Single-cell approaches have identified diverse human plaque cell phenotypes but their spatial distribution and interactions remain unclear. Here, intercellular communication patterns in human plaque microenvironments were mapped to reveal novel targets to prevent atherosclerotic events. Spatial transcriptomics (Visium, 10x) from 13 carotid plaques, and single-cell transcriptomics (cells = 51 981) were used to analyse cell phenotypes, cell trajectories, and intercellular communications. Cells contributing to plaque stability were explored using deconvolution of plaque bulk RNA-seq data (n = 78), histology, and survival analyses. Key cells and pathways were validated in apolipoprotein E (Apoe)-/- mice and in vitro. Genome-wide association study enrichment analyses were conducted using summary statistics of atherosclerotic diseases. LINCS L1000 data were used to explore drug repurposing. A fibroblast-like vascular smooth muscle cell (VSMC) phenotype associated with extracellular matrix formation pathways (validated in Apoe-/- mice) emerged as a key regulator of intra-plaque ligand-receptor signalling, in particular in the cap region. A higher proportion of fibroblast-like VSMCs was found in asymptomatics, associated with stable plaque features and predicted a lower risk of future events. Genes specific to this VSMC phenotype were enriched in coronary artery disease and myocardial infarction. Finally, compounds, which could induce key marker genes were identified and validated in vitro. This study provides the first comprehensive spatial transcriptomics map of cell communication in human plaque microenvironments. A pivotal role of a fibroblast-like VSMC, orchestrating intraplaque cell signalling and contributing to plaque stability, was identified. Targeting these cells might present promising novel avenues for therapies. Show less

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with extrapancreatic effects beyond glycemic control. Here we demonstrate unexpected effects of GIP signaling in the vasculature. GIP induces the expression of the proatherogenic cytokine osteopontin (OPN) in mouse arteries via local release of endothelin-1 and activation of CREB. Infusion of GIP increases plasma OPN concentrations in healthy individuals. Plasma endothelin-1 and OPN concentrations are positively correlated in patients with critical limb ischemia. Fasting GIP concentrations are higher in individuals with a history of cardiovascular disease (myocardial infarction, stroke) when compared with control subjects. GIP receptor (GIPR) and OPN mRNA levels are higher in carotid endarterectomies from patients with symptoms (stroke, transient ischemic attacks, amaurosis fugax) than in asymptomatic patients, and expression associates with parameters that are characteristic of unstable and inflammatory plaques (increased lipid accumulation, macrophage infiltration, and reduced smooth muscle cell content). While GIPR expression is predominantly endothelial in healthy arteries from humans, mice, rats, and pigs, remarkable upregulation is observed in endothelial and smooth muscle cells upon culture conditions, yielding a "vascular disease-like" phenotype. Moreover, the common variant rs10423928 in the GIPR gene is associated with increased risk of stroke in patients with type 2 diabetes. Show less