Single-cell analysis identifies the CNP/GC-B/cGMP axis as marker and regulator of modulated VSMCs in atherosclerosis

Moritz Lehners, Hannes Schmidt, Maria T. K. Zaldivia, Daniel Stehle, Michael Krämer, Andreas Peter, Julia Adler, Robert Lukowski, Susanne Feil and Robert Feil ()
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Moritz Lehners: University of Tübingen
Hannes Schmidt: University of Tübingen
Maria T. K. Zaldivia: University of Tübingen
Daniel Stehle: University of Tübingen
Michael Krämer: University of Tübingen
Andreas Peter: University Hospital Tübingen
Julia Adler: University of Tübingen
Robert Lukowski: University of Tübingen
Susanne Feil: University of Tübingen
Robert Feil: University of Tübingen

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract A balanced activity of cGMP signaling contributes to the maintenance of cardiovascular homeostasis. Vascular smooth muscle cells (VSMCs) can generate cGMP via three ligand-activated guanylyl cyclases, the NO-sensitive guanylyl cyclase, the atrial natriuretic peptide (ANP)-activated GC-A, and the C-type natriuretic peptide (CNP)-stimulated GC-B. Here, we study natriuretic peptide signaling in murine VSMCs and atherosclerotic lesions. Correlative profiling of pathway activity and VSMC phenotype at the single-cell level shows that phenotypic modulation of contractile VSMCs to chondrocyte-like plaque cells during atherogenesis is associated with a switch from ANP/GC‑A to CNP/GC‑B signaling. Silencing of the CNP/GC-B axis in VSMCs results in an increase of chondrocyte-like plaque cells. These findings indicate that the CNP/GC-B/cGMP pathway is a marker and atheroprotective regulator of modulated VSMCs, limiting their transition to chondrocyte-like cells. Overall, this study highlights the plasticity of cGMP signaling in VSMCs and suggests analogies between CNP-dependent remodeling of bone and blood vessels.

Date: 2025
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DOI: 10.1038/s41467-024-55687-9

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