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Anti-cancer therapy induces endothelial dysfunction in the human microcirculation that is prevented by VEGF-B overexpression

ABSTRACT: The present study is the first to demonstrate longitudinal declines in microvascular endothelial function in breast cancer patients undergoing anti-cancer therapy. Microvascular dysfunction persists for several months after treatment, which may have implications for elevated cardiovascular risk in cancer patients. Therapies with a high risk of cardiotoxicity (doxorubicin and trastuzumab) induce vasomotor impairments in healthy arterioles ex vivo. These findings highlight microvascular endothelial dysfunction as a consequence of anti-cancer therapy which may contribute to treatment-induced cardiotoxicity. The microcirculation represents a potential therapeutic target for intervention to prevent or predict adverse cardiovascular outcomes in breast cancer patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261326 | GEO | 2025/09/16

REPOSITORIES: GEO

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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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Anti-cancer therapy induces endothelial dysfunction in the human microcirculation that is prevented by VEGF-B overexpression

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