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Variants in genes encoding the soluble guanylyl cyclase (sGC) in platelets are associated with coronary artery disease (CAD) risk. Here, by using histology, flow cytometry and intravital microscopy, we show that functional loss of sGC in platelets of atherosclerosis-prone Ldlr−/− mice contributes to atherosclerotic plaque formation, particularly via increasing in vivo leukocyte adhesion to atherosclerotic lesions. In vitro experiments revealed that supernatant from activated platelets lacking sGC promotes leukocyte adhesion to endothelial cells (ECs) by activating ECs. Profiling of platelet-released cytokines indicated that reduced platelet angiopoietin-1 release by sGC-depleted platelets, which was validated in isolated human platelets from carriers of GUCY1A1 risk alleles, enhances leukocyte adhesion to ECs. Importantly, pharmacological sGC stimulation increased platelet angiopoietin-1 release in vitro and reduced leukocyte recruitment and atherosclerotic plaque formation in atherosclerosis-prone Ldlr−/− mice. Therefore, pharmacological sGC stimulation might represent a potential therapeutic strategy to prevent and treat CAD.

Additional file 1: Fig. S1. Treatment scheme of inhaled and systemic administered mosliciguat and of vehicle treatment in the minipig model. Each animal underwent eight unilateral ventilation cycles and animals were divided into two groups.

Soluble guanylate cyclase (sGC) is a protein that serves important functions in many different cell-types and tissues, including neurons and blood vessels. In neurons, the activity of sGC is important for healthy memory functioning, while in blood vessels sGC regulates vasodilation and endothelial cell functioning. Therefore, enhancing sGC activity could be a good strategy for not only improving memory functioning, but also improving (cerebro)vascular health, for example in patients suffering from vascular cognitive impairment. However, so far, very little research has focused on sGC for enhancing memory. Therefore, this thesis specifically investigated the memory enhancing potential of sGC modulators, pharmacological compounds that enhance sGC activity. It was found that sGC modulators can improve both long-term memory and short-term memory in rodents, via brain-specific mechanisms. Future research should therefore focus on disease modelling to further investigate sGC as a target for the treatment of cognitive impairments.