Key result
In a murine model, NO-GC-expressing activated fibroblasts in fibrotic myocardium originated from PDGFRβ- and Tcf21-positive precursors, rather than from resident pericytes or smooth muscle cells.
Why the study?
Little is known about the individual cardiac cell types that express NO-GC and the role of the enzyme in cardiac fibrosis.
Does angiotensin II-induced cardiac fibrosis alter the specific cellular expression pattern and lineage origin of NO-GC in the murine heart?
Does angiotensin II-induced cardiac fibrosis alter the specific cellular expression pattern and lineage origin of NO-GC in the murine heart?
NO-GC is expressed in pericytes and smooth muscle cells in normal myocardium, but emerges de novo in activated fibroblasts during fibrosis, providing a cellular basis for how NO-GC stimulators like vericiguat may mitigate fibrotic remodeling in heart failure.
Clarifies NO-GC+ fibroblast origins in murine fibrosis; hypothesis-generating for HF therapies, should not yet change practice.
NO-sensitive guanylyl cyclase (NO-GC) is involved in the (patho)physiology of the mammalian heart. However, little is known about the individual cardiac cell types that express NO-GC and the role of the enzyme in cardiac fibrosis. Here, we describe the cellular expression of NO-GC in healthy and fibrotic murine myocardium; these data were compared with scRNA-seq data. In healthy myocardium, NO-GC is strongly expressed in pericytes and smooth muscle cells but not in endothelial cells or cardiomyocytes. Angiotensin II induced cardiac hypertrophy and fibrosis; fibrotic lesions contained cells positive for NO-GC identified as activated fibroblasts. Lineage tracing indicates that NO-GC-expressing activated fibroblasts originate from PDGFRβ- and Tcf21-positive fibroblast precursors. Our data indicate NO-GC expression in cardiac pericytes and SMC in naive myocardium and in activated fibroblast in fibrotic heart tissue. NO-mediated signaling may modulate fibrotic responses underlying the action of NO-GC stimulators used in the therapy of heart failure.
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Kreutz et al. (2024) studied Cardiac fibrosis (n=78). Angiotensin II vs. 0.9% NaCl (saline) was evaluated on Cellular expression and lineage origin of NO-GC-expressing cells in fibrotic myocardium. In a murine model, NO-GC-expressing activated fibroblasts in fibrotic myocardium originated from PDGFRβ- and Tcf21-positive precursors, rather than from resident pericytes or smooth muscle cells.
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