Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada; Montreal Heart Institute, Montreal, Quebec, Canada.
Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada; Montreal Heart Institute, Montreal, Quebec, Canada.
Atherosclerosis. 2019 Apr;283:106-119. doi: 10.1016/j.atherosclerosis.2019.01.031. Epub 2019 Jan 31.
Our previous data showed that lymphatic function impairment occurs before the onset of atherosclerosis in mice and is precociously associated with a defect in the propelling capacity of the collecting lymphatic vessels. Concomitantly, we found that lymphatic transport can be restored in mice by systemic injections of a mutant form of VEGF-C (VEGF-C 152s), a growth factor known to increase mesenteric collecting lymphatic vessel pumping through a VEGFR-3-dependent mechanism in rats. In the present study, we aimed to determine whether and how early modulation of collecting lymphatic vessel function could restrain atherosclerosis onset and limit its progression.
Before the administration of a pro-atherosclerotic regimen, Ldlr mice at 6 weeks of age were injected intraperitoneally with VEGF-C 152s or PBS every other day for 4 weeks, fed on high fat diet (HFD) for an additional 8 weeks to promote plaque progression, and switched back on chow diet for 4 more weeks to stabilize the lesion.
Early treatment with VEGF-C first improved lymphatic molecular transport in 6-week-old Ldlr mice and subsequently limited plaque formation and macrophage accumulation, while improving inflammatory cell migration through the lymphatics in HFD-fed mice. The contraction frequency of the collecting lymphatic vessels was significantly increased following treatment throughout the whole atherosclerotic process and resulted in enhanced plaque stabilization. This early and maintained rescue of the lymphatic dysfunction was associated with an upregulation of VEGFR3 and FOXC2 expression on lymphatic endothelial cells.
These results suggest that early treatments that specifically target the lymphatic contraction capacity prior to lesion formation might be a novel therapeutic approach for the prevention and treatment of atherosclerosis.
我们之前的数据表明，在小鼠动脉粥样硬化发生之前就已经出现了淋巴管功能障碍，并且与收集淋巴管的推进能力缺陷过早相关。同时，我们发现通过全身注射一种突变形式的 VEGF-C（VEGF-C 152s）可以在小鼠中恢复淋巴管运输，这种生长因子已知通过大鼠中的 VEGFR-3 依赖性机制增加肠系膜收集淋巴管的泵血功能。在本研究中，我们旨在确定早期调节收集淋巴管功能是否以及如何抑制动脉粥样硬化的发生并限制其进展。
在给予促动脉粥样硬化方案之前，6 周龄的 Ldlr 小鼠每隔一天腹膜内注射 VEGF-C 152s 或 PBS，连续 4 周，然后给予高脂肪饮食（HFD）喂养 8 周以促进斑块进展，并切换回正常饮食 4 周以稳定病变。
早期用 VEGF-C 治疗首先改善了 6 周龄 Ldlr 小鼠的淋巴管分子运输，随后限制了斑块形成和巨噬细胞积累，同时改善了 HFD 喂养小鼠中炎症细胞通过淋巴管的迁移。在整个动脉粥样硬化过程中，收集淋巴管的收缩频率显著增加，导致斑块稳定性增强。这种对淋巴管功能障碍的早期和持续挽救与淋巴管内皮细胞上 VEGFR3 和 FOXC2 表达的上调有关。
这些结果表明，在病变形成之前专门针对淋巴管收缩能力的早期治疗可能是预防和治疗动脉粥样硬化的一种新的治疗方法。
