NO-sensitive guanylyl cyclase (NO-GC) regulates many different physiological functions through generation of cGMP and is also involved in the pathophysiology of several diseases. Vericiguat, a NO-GC stimulator, was shown to exert positive effects in heart failure patients by reducing hospitalizations and overall mortality (VICTORIA trial). However, little is known on the individual cardiac cell types that express NO-GC and the role of the enzyme in cardiac fibrosis and heart failure.

Using immunohistochemistry, we investigated the cellular expression of NO-GC in the murine heart. We also performed tdTomato-based lineage tracing using Cre recombinase under the control of different promoters. With this system, we also generated a pericyte-specific NO-GC knockout (PDGFRß-GCKO). We used angiotensin II-releasing mini-pumps to induce cardiac hypertrophy. To determine the cardiac pump function, we carried out hemodynamic measurements, using pressure-volume loops. In addition, we performed a dobutamine stress test.

In the heart, NO-GC is mainly expressed in cardiac pericytes, a PDGFRß-expressing cell type involved in the formation and function of capillaries as well as in cardiac remodeling after injury. In addition, NO-GC expression was identified in smooth muscle cells, but neither in endothelial cells nor fibroblasts. Angiotensin II-induced cardiac hypertrophy was paralleled by the development of fibrotic lesions, which were positive for NO-GC and PDGFRß immunosignals as well as PDGFRß-tdTomato-expressing cells. Pericyte-specific deletion of NO-GC (PDGFRß-GCKO) leads to elevated blood pressure determined with hemodynamic and tail-cuff measurements. In the angiotensin II-treated mice, PDGFRß-GCKO revealed reduced cardiac contractility and cardiac output. The resulting fibrosis was quantified with picrosirius red staining. Taken together, our preliminary experiments indicate that NO-GC in cardiac pericytes plays a role regarding contractility and fibrosis under pathophysiological conditions.