Zhou Wenxuan, Zhou Luning, Qi Zhiyong, Dai Shimo, Zhang Peng, Zhong Haoxuan, Xu Huajie, Zhao Xin, Lian Xiaoyu, Lin Jiaxiong, Wu Hongyi
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine, China.
Department of Infectious Disease, Zhongshan Hospital, Fudan University, Shanghai, China.
Eur J Pharmacol. 2025 Jul 15;999:177670. doi: 10.1016/j.ejphar.2025.177670. Epub 2025 Apr 24.
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 FeCl-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.
维立西呱是一种可溶性鸟苷酸环化酶（sGC）刺激剂，用于治疗慢性心力衰竭。维立西呱可在无NO的情况下直接与sGC结合，或稳定NO与sGC的结合，从而刺激cGMP生成。维立西呱与血小板活化密切相关。然而，维立西呱对体内血小板活化和血栓形成的确切作用仍有待阐明。
我们研究了维立西呱对激动剂诱导的血小板聚集、分泌、整合素αIIbβ3活化、铺展、血块收缩及体内血栓形成的影响，并阐明其潜在机制。此外，我们进行了全血凝集试验和微流控全血灌注试验，以确定维立西呱是否能减轻血栓形成。
维立西呱浓度依赖性地抑制人和小鼠血小板中激动剂诱导的聚集和ATP释放。维立西呱可抑制凝血酶诱导的P-选择素表达、整合素αIIbβ3活化、铺展和血块收缩。机制上，维立西呱与血小板中的sGC结合，激活cGMP/PKG信号通路以抑制血小板。维立西呱还可抑制野生型（WT）小鼠肠系膜小动脉中FeCl3损伤诱导的血栓形成及肺栓塞模型构建后的肺血管血栓形成。口服维立西呱2周也可减轻脑部血栓栓塞。
维立西呱通过与sGC结合并激活cGMP/PKG通路直接抑制体内血小板活化和血栓形成。除治疗慢性心力衰竭外，它在治疗血栓性疾病方面可能具有治疗优势。
