Endothelial dysfunction as a driver of microvascular injury in diabetic cardiomyopathy

Abstract

Diabetic cardiomyopathy (DCM) is a serious complication of diabetic mellitus that occurs independently of other known cardiac diseases and is associated with significant morbidity and mortality. Microvascular injury plays a central role in the pathogenesis of DCM, contributing to its hallmark features, such as cardiac contractile dysfunction and myocardial fibrosis. Current evidence points to endothelial dysfunction (ED) as the key contributor to the development of microvascular injury. Chronic hyperglycemia, hyperinsulinemia, and insulin resistance progressively promote ED, characterized by alterations in gene expression, shifts in endothelial cell (EC) subpopulation dynamics, and dysregulated crosstalk between EC and other cardiac cell types. Ultimately, these changes result in microvascular impairments such as chronic inflammation, EC loss leading to microvascular rarefaction, endothelial-to-mesenchymal transition (EndoMT) promoting myocardial fibrosis, and loss of vasodilatory function. If left uncorrected, these impairments will progress to contractile dysfunction and widespread myocardial fibrosis, manifesting as systolic heart failure. Over the past decade, single-cell RNA sequencing (scRNA-seq) has allowed for the transcriptional profiling of individual cells, enabling the identification of distinct subpopulations within the same cell type and providing deeper insights into cellular crosstalk under both normal and disease conditions. Although research on DCM using scRNA-seq remains an emerging field, studies have identified distinct EC subpopulations, their gene expression profiles, and their contributions to DCM pathogenesis. Moreover, scRNA-seq has revealed dysregulated interactions between ECs and other cardiac cell types in DCM. The expanding application of scRNA-seq holds significant promise for mapping EC subpopulation dynamics and communication pathways in DCM, which may ultimately support the development of novel EC-targeted therapeutic strategies against ED in this condition.

Keywords

Diabetic cardiomyopathy / single-cell RNA sequencing / endothelial dysfunction / microvascular injury / pericytes / cell-cell interactions

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