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Spatial Transcriptomic Profiling of the Type 2 Diabetic Coronary Microcirculation Reveals Heterogeneity Varied by Regions of the Heart [scRNA-seq]

ABSTRACT: Background: Coronary microvascular disease (CMD) is an early complication of type 2 diabetes (T2D) involving adverse endothelial and smooth muscle dysfunction, vascular remodeling, and alterations in mechanics, which culminate in impaired coronary blood flow. Recent data suggest that vascular layer-specific mechanisms, influenced by the surrounding myocardium, contribute to CMD. To investigate transcriptional differences potentially contributing to CMD, we used spatial and single cell transcriptomic profiling of the coronary microcirculation and surrounding myocardium across distinct heart subregions to identify new pathways to target. Methods: We combined single cell RNA profiling and spatial transcriptomics to examine transcriptional differences and molecular signatures of CMD in T2D mice. Results: Single cell RNA profiling and spatial transcriptomics revealed upregulation of genes linked to adipogenesis, fatty acid metabolism, and oxidative phosphorylation in T2D cell clusters and coronary microvascular-enriched regions. Using spatial transcriptomics, we also examined gene expression in coronary microvessel-enriched areas across different heart subregions. Interestingly, the most pronounced transcriptional differences between T2D and control coronary microvessels were observed in the left ventricular anterior wall, where inflammatory response pathways were downregulated in T2D mice. Genes associated with oxidative phosphorylation and fatty acid oxidation were significantly upregulated in T2D coronary microvessels within the left ventricular anterior wall.Conclusions: These intriguing data support the well-documented concept that cardiac metabolic inflexibility in T2D – characterized by reduced mitochondrial function, increased reliance on fatty acid oxidation, and impaired glucose utilization – contributes to oxidative stress and lipotoxicity, key drivers of heart failure. Furthermore, these data reveal previously unrecognized transcriptomic differences in coronary microvessels across spatially-distinct regions of the T2D heart, suggesting transcriptional heterogeneity in this critical vascular bed.

ORGANISM(S): Mus musculus

PROVIDER: GSE290095 | GEO | 2025/12/10

REPOSITORIES: GEO

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Project description:Background: Coronary microvascular disease (CMD) is an early complication of type 2 diabetes (T2D) involving adverse endothelial and smooth muscle dysfunction, vascular remodeling, and alterations in mechanics, which culminate in impaired coronary blood flow. Recent data suggest that vascular layer-specific mechanisms, influenced by the surrounding myocardium, contribute to CMD. To investigate transcriptional differences potentially contributing to CMD, we used spatial and single cell transcriptomic profiling of the coronary microcirculation and surrounding myocardium across distinct heart subregions to identify new pathways to target. Methods: We combined single cell RNA profiling and spatial transcriptomics to examine transcriptional differences and molecular signatures of CMD in T2D mice. Results: Single cell RNA profiling and spatial transcriptomics revealed upregulation of genes linked to adipogenesis, fatty acid metabolism, and oxidative phosphorylation in T2D cell clusters and coronary microvascular-enriched regions. Using spatial transcriptomics, we also examined gene expression in coronary microvessel-enriched areas across different heart subregions. Interestingly, the most pronounced transcriptional differences between T2D and control coronary microvessels were observed in the left ventricular anterior wall, where inflammatory response pathways were downregulated in T2D mice. Genes associated with oxidative phosphorylation and fatty acid oxidation were significantly upregulated in T2D coronary microvessels within the left ventricular anterior wall.Conclusions: These intriguing data support the well-documented concept that cardiac metabolic inflexibility in T2D – characterized by reduced mitochondrial function, increased reliance on fatty acid oxidation, and impaired glucose utilization – contributes to oxidative stress and lipotoxicity, key drivers of heart failure. Furthermore, these data reveal previously unrecognized transcriptomic differences in coronary microvessels across spatially-distinct regions of the T2D heart, suggesting transcriptional heterogeneity in this critical vascular bed.

Project description:The microcirculation serves crucial functions in adult heart that are distinct from those carried out by epicardial vessels. Microvessels are also governed by unique regulatory mechanisms, impairment of which leads to microvessel-specific pathology. While great progress has been made in understanding and treating coronary artery disease (CAD), there are few treatment options for patients with microvascular heart disease, primarily due to our limited understanding of underlying pathology. The advent of high-throughput analytical approaches of mRNA and protein expression in specific cells provides an opportunity to transform our understanding of microvessel biology and disease at the molecular level. Understanding responses of individual microvascular cells to the same physiological or pathophysiological stimuli requires the ability to isolate the specific cell types that comprise the functional units of the microcirculation in an adult heart, preferably from the same heart, to ensure that different cells have been exposed to the same in-vivo conditions. Furthermore, in-vitro functional and molecular analysis requires an integrated workflow that combines primary cell culture with high-throughput proteomic or transcriptomic analysis. Our goal was an integrated process for simultaneous isolation, culture, and proteomic profiling of the three main cell types comprising the microcirculation in adult mouse heart: endothelial cells (ECs), pericytes (PCs) and vascular smooth muscle cells (VSMCs). We developed an integrated platform for simultaneous isolation and culture of ECs, PCs and VSMCs from adult mouse heart, coupled with unbiased mass spectrometry (MS)-based characterization of protein expression in these cells. We defined microvascular cell proteomes, identified novel protein markers and confirmed established cell-specific markers. Isolating and analyzing microvascular cell types separately from the same preparation of adult mouse hearts allowed for separate investigations into the unique contributions of the different cell types to health and disease, and interactions among different cell types.

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Spatial Transcriptomic Profiling of the Type 2 Diabetic Coronary Microcirculation Reveals Heterogeneity Varied by Regions of the Heart [scRNA-seq]

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