Budbazar Enkhjargal, Balmes Aylin, Elliott Danielle, Peres Tintin Lisette, Kopp Timo, Feil Susanne, Feil Robert, Schäffer Tilman E, Seta Francesca
Vascular Biology Section, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, USA.
Institute of Applied Physics, University of Tübingen, Germany.
Vascul Pharmacol. 2025 Jun;159:107503. doi: 10.1016/j.vph.2025.107503. Epub 2025 May 16.
BACKGROUND & PURPOSE: Arterial stiffness, or loss of elastic compliance in large arteries, is an independent precursor of cardiovascular disease (CVD) [1] and dementia [2] for which currently there are no targeted therapies. We previously discovered that decreases in NO-sensitive guanylyl cyclase (NO-GC), the NO receptor which synthesizes cGMP, and in its target vasodilator-stimulated phosphoprotein (pVASP), lead to increased cytoskeletal actin polymerization in vascular smooth muscle cells (VSMCs) contributing to increased arterial stiffness [3]. In the current study, we tested whether activating NO-GC with an NO-GC activator (cinaciguat) modulates pVASP and cytoskeletal actin polymerization in VSMCs, thereby preventing obesity-induced arterial stiffness.
EXPERIMENTAL APPROACH & KEY RESULTS: Cinaciguat administration (5 mg/kg) to high fat, high sucrose diet (HFHS)-fed mice, our established model of arterial stiffness [4], (1) decreased pulse wave velocity, the in vivo index of arterial stiffness, without affecting blood pressure; (2) increased aortic pVASP levels; and (3) decreased actin polymerization, measured as ratio of filamentous (F) to globular (G) actin, compared to vehicle administration. In cultured VSMCs, cinaciguat (10 μmol/L) increased pVASP levels and decreased the F/G actin ratio at baseline and after stimulation with the cytokine tumor necrosis factor α (TNFα), which we previously showed is significantly increased in the aorta of HFHS-fed mice [4-6]. These effects were abrogated in aortas and VSMCs from mice with smooth muscle-specific cGKI deletion (cGKI), while being mimicked by a cell-permeable cGMP analog (8-Br-cGMP), which also decreased VSMC stiffness in vitro.
CONCLUSIONS & IMPLICATIONS: Collectively, our data strongly support the notion that pharmacological NO-GC activation would be beneficial in decreasing obesity-associated arterial stiffness by decreasing VSMC cytoskeletal actin hyper-polymerization. If translated to humans, NO-GC activators could become a viable approach to clinically treat arterial stiffness, which remains an unmet medical need.
动脉僵硬度，即大动脉弹性顺应性丧失，是心血管疾病（CVD）[1]和痴呆症[2]的独立先兆，目前尚无针对性治疗方法。我们之前发现，作为合成cGMP的一氧化氮（NO）受体的NO敏感型鸟苷酸环化酶（NO-GC）及其靶标血管舒张刺激磷蛋白（pVASP）水平降低，会导致血管平滑肌细胞（VSMC）中细胞骨架肌动蛋白聚合增加，进而导致动脉僵硬度增加[3]。在本研究中，我们测试了使用NO-GC激活剂（西那吉多）激活NO-GC是否能调节VSMC中的pVASP和细胞骨架肌动蛋白聚合，从而预防肥胖诱导的动脉僵硬度增加。
在我们已建立的动脉僵硬度模型[4]——高脂高糖饮食（HFHS）喂养的小鼠中给予西那吉多（5mg/kg），（1）降低了脉搏波速度，即动脉僵硬度的体内指标，且不影响血压；（2）提高了主动脉pVASP水平；（3）与给予载体相比，丝状（F）肌动蛋白与球状（G）肌动蛋白的比例所测得的肌动蛋白聚合减少。在培养的VSMC中，西那吉多（10μmol/L）在基线时以及在用细胞因子肿瘤坏死因子α（TNFα）刺激后提高了pVASP水平并降低了F/G肌动蛋白比例，我们之前表明在HFHS喂养小鼠的主动脉中该比例显著增加[4-6]。这些效应在平滑肌特异性cGKI缺失（cGKI）小鼠的主动脉和VSMC中被消除，而可渗透细胞的cGMP类似物（8-溴-cGMP）模拟了这些效应，其在体外也降低了VSMC僵硬度。
总体而言，我们的数据有力地支持了这样一种观点，即通过减少VSMC细胞骨架肌动蛋白过度聚合，药理学上激活NO-GC对降低肥胖相关的动脉僵硬度有益。如果能转化应用于人类，NO-GC激活剂可能成为临床上治疗动脉僵硬度的可行方法，而动脉僵硬度仍是未满足的医疗需求。
