Department of Experimental Pharmacology, Chair of Pharmacology, Jagiellonian University Medical College, 16 Grzegórzecka Street, 31-531 Krakow, Poland.
Prostaglandins Other Lipid Mediat. 2012 Aug;98(3-4):107-15. doi: 10.1016/j.prostaglandins.2012.02.002. Epub 2012 Mar 24.
Adequate endothelial production of nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF), and prostacyclin (PGI₂) is critical to the maintenance of vascular homeostasis. However, it is not clear whether alterations in each of these vasodilatory pathways contribute to the impaired endothelial function in murine atherosclerosis. In the present study, we analyze the alterations in NO-, EDHF- and PGI₂-dependent endothelial function in the thoracic aorta in relation to the development of atherosclerotic plaques in apoE/LDLR⁻/⁻ mice. We found that in the aorta of 2-month-old apoE/LDLR⁻/⁻ mice there was no lipid deposition, subendothelial macrophage accumulation; and matrix metalloproteinase (MMP) activity was low, consistent with the absence of atherosclerotic plaques. Interestingly, at this stage the endothelium was already activated and hypertrophic as evidenced by electron microscopy, while acetylcholine-induced NO-dependent relaxation in the thoracic aorta was impaired, with concomitant upregulation of cyclooxygenase-2 (COX-2)/PGI₂ and EDHF (epoxyeicosatrienoic acids, EETs) pathways. In the aorta of 3-6-month-old apoE/LDLR⁻/⁻ mice, lipid deposition, macrophage accumulation and MMP activity in the intima were gradually increased, while impairment of NO-dependent function and compensatory upregulation of COX-2/PGI₂ and EDHF pathways were more accentuated. These results suggest that impairment of NO-dependent relaxation precedes the development of atherosclerosis in the aorta and early upregulation of COX-2/PGI₂ and EDHF pathways may compensate for the loss of the biological activity of NO.
足够的内皮细胞产生一氧化氮（NO）、内皮衍生超极化因子（EDHF）和前列环素（PGI₂）对于维持血管内环境稳定至关重要。然而，目前尚不清楚这些血管舒张途径中的每一种改变是否会导致小鼠动脉粥样硬化中内皮功能的损害。在本研究中，我们分析了在 apoE/LDLR⁻/⁻小鼠动脉粥样硬化斑块形成过程中，NO、EDHF 和 PGI₂依赖性内皮功能的改变。我们发现，在 2 个月大的 apoE/LDLR⁻/⁻小鼠的主动脉中，没有脂质沉积、内皮下巨噬细胞积聚；基质金属蛋白酶（MMP）活性较低，与无动脉粥样硬化斑块相一致。有趣的是，在这个阶段，内皮细胞已经被激活并且肥大，这可以通过电子显微镜来证明，而胸主动脉中乙酰胆碱诱导的 NO 依赖性松弛已经受损，同时伴有环氧合酶-2（COX-2）/PGI₂和 EDHF（环氧化二十碳三烯酸，EETs）途径的上调。在 3-6 个月大的 apoE/LDLR⁻/⁻小鼠的主动脉中，内膜中的脂质沉积、巨噬细胞积聚和 MMP 活性逐渐增加，而 NO 依赖性功能的损害和 COX-2/PGI₂和 EDHF 途径的代偿性上调更为明显。这些结果表明，NO 依赖性松弛功能的损害先于主动脉粥样硬化的发生，COX-2/PGI₂和 EDHF 途径的早期上调可能代偿了 NO 生物学活性的丧失。
