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ORIGINAL RESEARCH article

Front. Cardiovasc. Med.

Sec. Cardiovascular Biologics and Regenerative Medicine

Volume 12 - 2025 | doi: 10.3389/fcvm.2025.1634645

This article is part of the Research TopicDeciphering Cardiovascular Cell Heterogeneity with Single Cell RNA SequencingView all articles

Single-cell transcriptomic analysis of the human vascular atlas provides new insights into vasorelaxation redundancy and heterogeneity

Provisionally accepted
Elisa  AvolioElisa Avolio1Sarah  PearceSarah Pearce1Dave  WambekeDave Wambeke2Paolo  MadedduPaolo Madeddu1*
  • 1University of Bristol, Bristol, United Kingdom
  • 2DiaMedica Therapeutics, Minnetonka, United States

The final, formatted version of the article will be published soon.

Background: Endothelial cells (ECs) induce vascular smooth muscle cells (VSMCs) relaxation via nitric oxide (NO), prostacyclin (PGI₂) and hyperpolarizing factors. Recent whole-genomic, single-cell transcriptomic analysis of human vascular cells has revealed angiotypic heterogeneity. However, it remains unknown whether vasorelaxant mediators reiterate this pattern. Working hypothesis: The expression of “sentinel” gene transcripts provides a first insight into angiotypic and organotypic heterogeneity of vasorelaxation. Methods: The expression of NO- and PGI2-generating enzymes and potassium channels was evaluated by analyzing single-cell RNA-sequencing data derived from the Human Vascular Cell Atlas. The data were transformed into a Seurat object (ShinyCell) and processed using the RStudio software. The results were visualized through uniform manifold approximation (UMAP) and projection representations of single-cell profiles. Results: NO synthase (NOS3) expression differed across EC subpopulations, with the highest enrichment in spleen littoral ECs, followed by venous, arterial, and capillary ECs. PGI2 synthase (PTGIS) demonstrated the highest frequency in arterial and venous ECs and VSMCs. At the same time, it was low in capillary, littoral, and lymphatic ECs and pericytes. The PGI2 receptor gene (PTGIR) was expressed in vascular mural cells. A marked angiotypic heterogeneity was noted regarding potassium channels. Overall, the gene transcripts mentioned above were rarely co-expressed. Comparing two cohorts aged 20 to 49 and 50 to 80 revealed NOS3 expression was less frequent in venous and littoral ECs of older individuals. In contrast, arterial and capillary ECs were modestly affected by age. PTGIS frequency was elevated with aging in VSMCs and, to a lesser extent, in venous and arterial ECs. The KCNMA1 gene, which encodes the big potassium channel alpha subunit 1, was almost doubled in the VSMCs from the older group. Finally, organotypic differences were identified in vascular cells derived from the coronary arteries, brain, and uterus. Conclusion: This initial report indicates a striking heterogeneity in the expression of genes encoding vasorelaxant pathways in human vascular cells, with age exerting angiotypic influences. Reiteration on a larger number of cells and genes, as well as validation of data using post-transcriptional methods, is warranted to firmly confirm the hypothesis about redundant heterogeneity of vasorelaxant mechanisms.

Keywords: DiaMedica Therapeutics, Minnetonka, MN, USA (D.W.) AchR: acetylcholine receptor, eNOS: Endothelial Nitric Oxide Synthase, B1R / B2R: bradykinin receptors, sGC: soluble guanylate cyclase, GTP: guanosine triphosphate, PKG: protein kinase G, PGH2: Prostaglandin H2, PGHS: prostaglandin H synthase

Received: 24 May 2025; Accepted: 15 Jul 2025.

Copyright: © 2025 Avolio, Pearce, Wambeke and Madeddu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Paolo Madeddu, University of Bristol, Bristol, United Kingdom

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