The soluble guanylate cyclase (sGC) stimulator vericiguat inhibits platelet activation and thrombosis

Vericiguat, a soluble guanylate cyclase (sGC) stimulator, is used to treat chronic heart failure. Vericiguat can directly bind to the sGC in the absence of NO or stabilize the binding of NO to sGC, thereby stimulating cGMP production. Vericiguat correlates closely with the platelet activation. However, the precise effect of vericiguat on platelet activation and thrombosis in vivo remains to be elucidated.

We investigated the effects of vericiguat on agonist-induced platelet aggregation, secretion, integrin αIIbβ3 activation, spreading, clot retraction, and thrombus formation in vivo, elucidating the underlying mechanisms. Additionally, we performed whole blood aggregometry and Microfluidic whole-blood perfusion assay to determine whether vericiguat could alleviate thrombosis.

Vericiguat concentration-dependently inhibited aggregation and ATP release induced by agonists both in human and mouse platelets. P-selection expression, integrin αIIbβ3 activation, spreading, and clot retraction induced by thrombin were all inhibited by vericiguat. Mechanistically, vericiguat bound to the sGC in platelets, avtivating the cGMP/PKG signaling pathway to inhibit the platelet. Vericiguat also inhibited the FeCl₃-injured thrombus formation in mesenteric arterioles in wild-type (WT) mice and pulmonary vascular thrombi after constructing the pulmonary embolism model. Oral administration of vericiguat for 2 weeks attenuated thromboembolism in brain, too.

Vericiguat directly inhibits platelet activation and thrombosis in vivo by binding to the sGC and activating cGMP/PKG pathway. In addition to the treatment for chronic heart failure, it may have therapeutic advantages in treating thrombotic diseases.