Tatin Florence, Renaud-Gabardos Edith, Godet Anne-Claire, Hantelys Fransky, Pujol Francoise, Morfoisse Florent, Calise Denis, Viars Fanny, Valet Philippe, Masri Bernard, Prats Anne-Catherine, Garmy-Susini Barbara
I2MC INSERM UMR 1048, Toulouse Cedex, France.
UMS 006, INSERM, UPS, F-31432 Toulouse, France.
JCI Insight. 2017 Jun 15;2(12). doi: 10.1172/jci.insight.93887.
Lymphatic endothelium serves as a barrier to control fluid balance and immune cell trafficking to maintain tissue homeostasis. Long-term alteration of lymphatic vasculature promotes edema and fibrosis, which is an aggravating factor in the onset of cardiovascular diseases such as myocardial infarction. Apelin is a bioactive peptide that plays a central role in angiogenesis and cardiac contractility. Despite an established role of apelin in lymphangiogenesis, little is known about its function in the cardiac lymphatic endothelium. Here, we show that apelin and its receptor APJ were exclusively expressed on newly formed lymphatic vasculature in a pathological model of myocardial infarction. Using an apelin-knockout mouse model, we identified morphological and functional defects in lymphatic vasculature associated with a proinflammatory status. Surprisingly, apelin deficiency increased the expression of lymphangiogenic growth factors VEGF-C and VEGF-D and exacerbated lymphangiogenesis after myocardial infarction. Conversely, the overexpression of apelin in ischemic heart was sufficient to restore a functional lymphatic vasculature and to reduce matrix remodeling and inflammation. In vitro, the expression of apelin prevented the alteration of cellular junctions in lymphatic endothelial cells induced by hypoxia. In addition, we demonstrated that apelin controls the secretion of the lipid mediator sphingosine-1-phosphate in lymphatic endothelial cells by regulating the level of expression of sphingosine kinase 2 and the transporter SPNS2. Taken together, our results show that apelin plays a key role in lymphatic vessel maturation and stability in pathological settings. Thus, apelin may represent a novel candidate to prevent pathological lymphatic remodeling in diseases.
淋巴管内皮作为一道屏障，控制液体平衡和免疫细胞运输，以维持组织稳态。淋巴管系统的长期改变会促进水肿和纤维化，这是心肌梗死等心血管疾病发病的一个加重因素。Apelin是一种生物活性肽，在血管生成和心脏收缩中起核心作用。尽管Apelin在淋巴管生成中的作用已得到确立，但其在心脏淋巴管内皮中的功能却知之甚少。在此，我们表明，在心肌梗死的病理模型中，Apelin及其受体APJ仅在新形成的淋巴管系统中表达。使用Apelin基因敲除小鼠模型，我们发现淋巴管系统存在与促炎状态相关的形态和功能缺陷。令人惊讶的是，Apelin缺乏会增加淋巴管生成生长因子VEGF-C和VEGF-D的表达，并加剧心肌梗死后的淋巴管生成。相反，缺血心脏中Apelin的过表达足以恢复功能性淋巴管系统，并减少基质重塑和炎症。在体外，Apelin的表达可防止缺氧诱导的淋巴管内皮细胞中细胞连接的改变。此外，我们证明Apelin通过调节鞘氨醇激酶2和转运体SPNS2的表达水平来控制淋巴管内皮细胞中脂质介质鞘氨醇-1-磷酸的分泌。综上所述，我们的结果表明，Apelin在病理情况下的淋巴管成熟和稳定性中起关键作用。因此，Apelin可能是预防疾病中病理性淋巴管重塑的一个新候选物。
