Lehners Moritz, Schmidt Hannes, Zaldivia Maria T K, Stehle Daniel, Krämer Michael, Peter Andreas, Adler Julia, Lukowski Robert, Feil Susanne, Feil Robert
Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany.
Department for Diagnostic Laboratory Medicine, Institute for Clinical Chemistry and Pathobiochemistry, University Hospital Tübingen, Tübingen, Germany.
Nat Commun. 2025 Jan 15;16(1):429. doi: 10.1038/s41467-024-55687-9.
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.
cGMP信号的平衡活动有助于维持心血管稳态。血管平滑肌细胞（VSMCs）可通过三种配体激活的鸟苷酸环化酶生成cGMP，即一氧化氮敏感性鸟苷酸环化酶、心房利钠肽（ANP）激活的GC-A以及C型利钠肽（CNP）刺激的GC-B。在此，我们研究小鼠VSMCs和动脉粥样硬化病变中的利钠肽信号传导。在单细胞水平上对通路活性和VSMC表型进行相关分析表明，动脉粥样硬化形成过程中收缩性VSMCs向软骨细胞样斑块细胞的表型调节与从ANP/GC-A信号向CNP/GC-B信号的转变相关。VSMCs中CNP/GC-B轴的沉默导致软骨细胞样斑块细胞增加。这些发现表明，CNP/GC-B/cGMP通路是调节性VSMCs的一个标志物和抗动脉粥样硬化保护调节因子，限制了它们向软骨细胞样细胞的转变。总体而言，本研究突出了VSMCs中cGMP信号的可塑性，并提示了CNP依赖的骨骼和血管重塑之间的相似性。
