Analysis of cellular NO-GC expression in the murine heart and lineage determination in angiotensin II-induced fibrosis.

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.