VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue
VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue
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DOI：
10.1182/blood-2012-04-421040
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发表时间：
2012-11-29
期刊：
影响因子：
20.3
通讯作者：
Phillipson, Mia
中科院分区：
文献类型：
--
作者：
Christoffersson, Gustaf;Vagesjo, Evelina;Phillipson, Mia
白细胞在血管生长部位的募集和保留对于适当的血管生成和随后的组织灌注至关重要。虽然对再生医学的许多方面至关重要，但白细胞募集到血管生成部位的机制和在血管生成部位的作用尚未完全理解。在这项研究中，我们研究了吸引白细胞到无血管移植胰岛的信号和白细胞在植入部位的作用。小鼠胰岛同基因移植到肌肉后不久，血管生成刺激因子VEGF-A的表达升高。在移植部位观察到高水平的白细胞，主要是CD 11b（+）/Gr-1（+）/CXCR 4（hi）中性粒细胞，而VEGF-A缺陷的胰岛在移植时仅募集一半的白细胞。急性肌肉VEGF-A暴露增加白细胞外渗，但不增加SDF-1 α水平。VEGF-A募集的中性粒细胞表达的MMP-9的量是炎症刺激募集的中性粒细胞的10倍。移植到MMP-9缺陷小鼠的胰岛的再血管化受损，因为血管最初未能穿透移植物，2周后血管供应仍然受到干扰。这项研究表明，VEGF-A招募了一个CD 11b（+）/Gr-1（+）中性粒细胞的促血管生成循环亚群，这些中性粒细胞是CXCR 4（hi），并提供大量的效应蛋白MMP-9，这是移植后胰岛血管重建和功能整合所需的。（血。2012; 120（23）：4653-4662）
Recruitment and retention of leukocytes at a site of blood vessel growth are crucial for proper angiogenesis and subsequent tissue perfusion. Although critical for many aspects of regenerative medicine, the mechanisms of leukocyte recruitment to and actions at sites of angiogenesis are not fully understood. In this study, we investigated the signals attracting leukocytes to avascular transplanted pancreatic islets and leukocyte actions at the engraftment site. Expression of the angiogenic stimulus VEGF-A by mouse pancreatic islets was elevated shortly after syngeneic transplantation to muscle. High levels of leukocytes, predominantly CD11b(+)/Gr-1(+)/CXCR4(hi) neutrophils, were observed at the site of engraftment, whereas VEGF-A-deficient islets recruited only half of the amount of leukocytes when transplanted. Acute VEGF-A exposure of muscle increased leukocyte extravasation but not the levels of SDF-1 alpha. VEGF-A-recruited neutrophils expressed 10 times higher amounts of MMP-9 than neutrophils recruited to an inflammatory stimulus. Revascularization of islets transplanted to MMP-9-deficient mice was impaired because blood vessels initially failed to penetrate grafts, and after 2 weeks vascularity was still disturbed. This study demonstrates that VEGF-A recruits a proangiogenic circulating subset of CD11b(+)/Gr-1(+) neutrophils that are CXCR4(hi) and deliver large amounts of the effector protein MMP-9, required for islet revascularization and functional integration after transplantation. (Blood. 2012; 120(23):4653-4662)