Modulation of macrophage polarization with acute administration of Vericiguat after myocardial infarction

Vericiguat (Merck, marketed as Verquvo) is a soluble guanylate cyclase stimulator that is Food and Drug Administration-approved for use in heart failure patients with reduced or mildly reduced ejection fraction (HFrEF and HFmrEF) to decrease heart failure hospitalization and cardiovascular mortality. We hypothesized that earlier administration of vericiguat post-myocardial infarction (MI) would reduce the workload of the viable cardiomyocytes, leading to an earlier switch toward anti-inflammatory macrophages and reduced adverse remodeling. Male and female C57BL/6J mice (<i>n</i> = 6/sex/group) underwent permanent occlusion of the left anterior descending coronary artery, followed by implantation of a subcutaneous osmotic minipump (vericiguat or saline) 24 h later. Echocardiography and histological assessment were performed for cardiomyocyte size (wheat germ agglutinin), vascularity (<i>Griffonia simplicifolia</i> lectin I), and collagen area fraction (Picrosirius red). Macrophages were isolated from the infarct at <i>day 3</i> post-MI and conditioned media was collected. Although cardiomyocyte size did not significantly differ between treatment groups, female drug-treated mice trended toward smaller cardiomyocytes in the border zone compared with males. Macrophage numbers were not affected, however, proteomic analysis demonstrated a proangiogenic phenotype with vericiguat. In vitro stimulation of endothelial cells with the macrophage-conditioned media from female drug-treated mice demonstrated a more organized and robust tubule network. Drug-treated females trended toward greater collagen in the infarct at <i>day 7</i> post-MI, whereas drug-treated males had decreased vessel density in the remote area compared with controls. Despite the molecular changes observed, no significant differences in cardiac function were observed at <i>day 7</i> post-MI. Our data demonstrate that acute administration of vericiguat post-MI stimulates macrophages toward a proangiogenic phenotype that was more exaggerated in females.<b>NEW & NOTEWORTHY</b> Acute administration of Vericiguat after myocardial infarction alters macrophage phenotype but not cell numbers. Macrophages from Vericiguat-treated mice led to more robust endothelial cell tubule formation. Acute administration of Vericiguat stimulates macrophages toward a proangiogenic phenotype that was more exaggerated in females.