Department of Clinical Pharmacology, University of Groningen, and University Medical Center Groningen, Groningen, The Netherlands.
Am J Physiol Heart Circ Physiol. 2013 Mar 1;304(5):H709-18. doi: 10.1152/ajpheart.00543.2012. Epub 2012 Dec 21.
Growth differentiation factor 15 (GDF15) is an independent predictor of cardiovascular disease, and increased GDF15 levels have been associated with endothelial dysfunction in selected patients. We therefore investigated whether GDF15 modulates endothelial function in aortas of wild-type (WT) and GDF15 knockout (KO) mice. Vascular contractions to phenylephrine and relaxation to ACh were assessed in aortas obtained from healthy WT and GDF15 KO mice. The effects of GDF15 pretreatment and the involvement of ROS or caveolae were determined. Phenylephrine-induced contractions and ACh-mediated relaxations were similar in WT and GDF15 KO mice. Pretreatment with GDF15 inhibited contraction and relaxation in both groups. Inhibition of contraction by GDF15 was absent in denuded vessels or after blockade of nitric oxide (NO) synthase. Relaxation in WT mice was mediated mainly through NO and an unidentified endothelium-derived hyperpolarizin factor (EDHF), whereas GDF15 KO mice mainly used prostaglandins and EDHF. Pretreatment with GDF15 impaired relaxation in WT mice by decreasing NO; in GDF15 KO mice, this was mediated by decreased action of prostaglandins. Disruption of caveolae resulted in a similar inhibition of vascular responses as GDF15. ROS inhibition did not affect vascular function. In cultured endothelial cells, GDF15 pretreatment caused a dissociation between caveolin-1 and endothelial NO synthase. In conclusion, GDF15 impairs aortic contractile and relaxing function through an endothelium-dependent mechanism involving altered caveolar endothelial NO synthase signaling.
生长分化因子 15（GDF15）是心血管疾病的独立预测因子，在一些选定的患者中，GDF15 水平的升高与内皮功能障碍有关。因此，我们研究了 GDF15 是否可以调节野生型（WT）和 GDF15 敲除（KO）小鼠主动脉的内皮功能。在从健康 WT 和 GDF15 KO 小鼠获得的主动脉中评估了对苯肾上腺素的血管收缩和对 ACh 的舒张作用。确定了 GDF15 预处理的效果以及 ROS 或 caveolae 的参与。WT 和 GDF15 KO 小鼠之间的苯肾上腺素诱导的收缩和 ACh 介导的舒张作用相似。GDF15 预处理抑制了两组的收缩和舒张。在裸血管或阻断一氧化氮（NO）合酶后，GDF15 抑制收缩作用消失。WT 小鼠的舒张主要通过 NO 和一种未识别的内皮衍生超极化因子（EDHF）介导，而 GDF15 KO 小鼠主要使用前列腺素和 EDHF。GDF15 预处理通过减少 NO 来损害 WT 小鼠的舒张；在 GDF15 KO 小鼠中，这是通过减少前列腺素的作用来介导的。破坏 caveolae 导致血管反应的抑制类似于 GDF15。ROS 抑制不影响血管功能。在培养的内皮细胞中，GDF15 预处理导致 caveolin-1 与内皮型一氧化氮合酶分离。总之，GDF15 通过涉及改变 caveolar 内皮型一氧化氮合酶信号的内皮依赖性机制损害主动脉收缩和舒张功能。
