Inhibition of Angiopoietin-2 Production by Myofibrocytes Inhibits Neointimal Hyperplasia After Endoluminal Injury in Mice.
Inhibition of Angiopoietin-2 Production by Myofibrocytes Inhibits Neointimal Hyperplasia After Endoluminal Injury in Mice.
复制标题
抑制肌纤维细胞生成血管生成素 2 可抑制小鼠腔内损伤后的新内膜增生
DOI：
10.3389/fimmu.2018.01517
复制
发表时间：
2018
影响因子：
7.3
通讯作者：
Dorling A
中科院分区：
文献类型：
--
作者：
Chen D;Li K;Tham EL;Wei LL;Ma N;Dodd PC;Luo Y;Kirchhofer D;McVey JH;Dorling A
纤维细胞是涉及伤口愈合、修复和纤维化的髓系细胞。我们以前的研究表明，纤维细胞在血管损伤后被动员到循环中，包括同种异体移植后发生的免疫介导的损伤。炎症性血管损伤的常见反应是内膜增生（IH），其与血管重塑一起导致血流进行性损失、下游缺血和终末器官纤维化。这形成了移植动脉硬化和包括血管成形术后再狭窄的其他疾病的病理基础。在调查纤维细胞是否有助于IH，我们以前表明，表达平滑肌肌动蛋白和CD 31的亚群被招募到损伤部位，并在新生内膜中积累。通过这些“CD 31+肌纤维细胞”表达组织因子（TF）是进行性新生内膜扩张所需的，使得TF抑制在损伤后第28天将新生内膜限制为单层细胞。本研究的目的是确定TF下游的病理生理介质，有助于肌纤维细胞协调的IH。我们首先表明，肌纤维细胞构成了损伤后28天的新生内膜的重要组成部分。使用先前定义的过继转移模型，我们然后表明，CD 31+肌纤维细胞得到招募早期损伤部位，该模型允许操作过继转移细胞研究IH如何发展。在证实了TF对过继转移细胞的抑制可以防止IH后，我们发现TF主要通过产生凝血酶诱导肌纤维细胞分泌血管生成素-2，这直接刺激增殖，抑制凋亡，并诱导新生内膜细胞（包括非纤维细胞）产生CXCL-12，所有这些都促进体内进行性IH。在孵育之前通过抑制血管生成素-2分泌或阻断过继转移的纤维细胞上的TIE-2信号传导抑制IH。这些新的数据表明，血管生成素-2生产的早期招募的肌纤维细胞严重影响的发展，血管损伤后的IH，并提出了新的治疗途径的探索。
Fibrocytes are myeloid lineage cells implicated in wound healing, repair, and fibrosis. We previously showed that fibrocytes are mobilized into the circulation after vascular injury, including the immune-mediated injury that occurs after allogeneic transplantation. A common response to inflammatory vascular injury is intimal hyperplasia (IH), which, alongside vascular remodeling, results in progressive loss of blood flow, downstream ischemia, and end-organ fibrosis. This forms the pathological basis of transplant arteriosclerosis and other diseases including post-angioplasty re-stenosis. In investigating whether fibrocytes contribute to IH, we previously showed that subpopulations expressing smooth muscle actin and CD31 are recruited to the site of injury and accumulate in the neointima. Expression of tissue factor (TF) by these “CD31+ myofibrocytes” is needed for progressive neointimal expansion, such that TF inhibition limits the neointima to a single layer of cells by day 28 post-injury. The aim of this study was to determine pathophysiological mediators downstream of TF that contribute to myofibrocyte-orchestrated IH. We first show that myofibrocytes make up a significant component of the neointima 28 days following injury. Using a previously defined adoptive transfer model, we then show that CD31+ myofibrocytes get recruited early to the site of injury; this model allows manipulations of the adoptively transferred cells to study how IH develops. Having confirmed that inhibition of TF on adoptively transferred cells prevents IH, we then show that TF, primarily through the generation of thrombin, induces secretion of angiopoietin-2 by myofibrocytes and this directly stimulates proliferation, inhibits apoptosis, and induces CXCL-12 production by neointimal cells, including non-fibrocytes, all of which promote progressive IH in vivo. Prior incubation to inhibit angiopoietin-2 secretion by or block TIE-2 signaling on adoptively transferred fibrocytes inhibits IH. These novel data indicate that angiopoietin-2 production by early recruited myofibrocytes critically influences the development of IH after vascular injury and suggest new therapeutic avenues for exploration.
登录
查看更多内容
DOI：
10.1161/atvbaha.111.223701
发表时间：
2011-06
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Nemenoff RA;Horita H;Ostriker AC;Furgeson SB;Simpson PA;VanPutten V;Crossno J;Offermanns S;Weiser-Evans MC
通讯作者：
Weiser-Evans MC
影响因子：
82.9
作者：
Shimizu, K;Sugiyama, S;Mitchell, RN
通讯作者：
Mitchell, RN
DOI：
10.1161/01.atv.0000250606.70669.14
发表时间：
2007-02-01
影响因子：
8.7
作者：
Shiba, Yuji;Takahashi, Masafumi;Ikeda, Uichi
通讯作者：
Ikeda, Uichi
影响因子：
37.8
作者：
Iwata, Hiroshi;Manabe, Ichiro;Nagai, Ryozo
通讯作者：
Nagai, Ryozo
影响因子：
56.9
作者：
Maisonpierre, PC;Suri, C;Yancopoulos, GD
通讯作者：
Yancopoulos, GD