Mechanism for IL-1β-mediated neovascularization unmasked by IL-1β knock-out mice
Mechanism for IL-1β-mediated neovascularization unmasked by IL-1β knock-out mice
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DOI：
10.1016/j.yjmcc.2004.01.006
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发表时间：
2004-04-01
影响因子：
5
通讯作者：
Matsubara, H
中科院分区：
文献类型：
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作者：
Amano, K;Okigaki, M;Matsubara, H
我们报道白细胞介素-1 β（IL-1 β）上调心脏血管内皮生长因子（VEGF）和血管内皮生长因子受体-2（VEGFR-2）的表达，这增加了IL-1 β在VEGF介导的新血管形成中发挥重要作用的可能性。在这项研究中，我们使用IL-1 β基因敲除（-/-）小鼠研究了缺血诱导的新生血管形成的细胞机制。与野生型小鼠相比，IL-1 β-/-小鼠缺血后肢的血液灌注恢复明显受损（减少43%）。CD 31（+）血管数和Ki-67（+）新生毛细血管数分别减少44%和68%（P < 0.01）。IL-1 β表达定位于缺血肢体肌肉的毛细血管。在IL-1 β-/-小鼠中，缺血诱导的缺氧诱导因子1 α（HIF-1 α）、VEGF及其受体VEGFR-2和血管细胞粘附分子-1（VCAM-1）的表达明显受到抑制。后肢缺血诱导野生型小鼠外周血中CD 34（-）/B220（-）/CD 3（-）/Flk-1（+）造血干细胞群体增加（占总核细胞的1.22%），而在IL-1 β-/-小鼠中这种增加仅为0.09%。向野生型小鼠注射IL-1 β蛋白显著增加外周血中CD 34（-）/B220（-）/CD 3（-）/Flk-1（+）细胞群的比例（从0.03%至0.7%），与内皮细胞数量的增加相关。这种IL-1 β介导的细胞数量增加可通过共注射抗VEGF抗体阻断。CD 34（-）/B220（-）CD 3（-）Flk-1（+）细胞在体内和体外转分化为表达eNOS和CD 31的内皮细胞。本研究表明，IL-1 β通过以VEGF依赖性方式动员CD 34（-）/B220（-）CD 3（-）Flk-1（+）内皮前体细胞以及通过上调内皮细胞上VEGF、VEGFR-2和粘附分子的表达，在缺血诱导的新生血管形成中起关键作用。(C)2003爱思唯尔有限公司。保留所有权利。
We have reported that interleukin-1 beta (IL-1beta) upregulates cardiac expression of vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2), raising the possibility that IL-1beta plays an important role in VEGF-mediated neovascularization. In this study, we examined the cellular mechanism for ischemia-induced neovascularization using IL-1beta knock-out (-/-) mice. Recovery of blood perfusion in ischemic hindlimb in IL-1beta-/- mice was markedly (43% decrease) impaired as compared with the wild-type mice. CD31(+) vessel numbers and Ki-67(+) neo-capillaries were significantly (P < 0.01) decreased 44% and 68%, respectively. IL-1beta expression was localized in the capillary vessels in ischemic limb muscles. Ischemia-induced expressions of hypoxia-inducible factor 1 alpha (HIF-1alpha), VEGF, its receptor VEGFR-2 and vascular cell adhesion molecule-1 (VCAM-1) were markedly inhibited in the IL-1beta-/- mice. Hindlimb ischemia-induced an increase (1.22% out of total nuclear cell) in CD34(-)/B220(-)/CD3(-)/Flk-1(+) hematopoietic stem cell population in peripheral blood in the wild-type mice, whereas in the IL-1beta-/- mice such increase was only 0.09%. Injection of IL-1beta protein into the wild-type mice markedly increased the ratio of the CD34(-)/B220(-)/CD3(-)/Flk-1(+) cell population (from 0.03% to 0.7%) in the peripheral blood associated with an increase in the number of endothelial cells. Such IL-1beta-mediated increases in cell numbers were blocked by co-injection of anti-VEGF antibody. CD34(-)/B220(-)CD3(-)Flk-1(+) cells trans-differentiated into eNOS- and CD31-expressing endothelial cells in vivo and in vitro. This study demonstrates that IL-1beta plays a key role in ischemia-induced neovascularization by mobilizing CD34(-)/B220(-)CD3(-)Flk-1(+) endothelial precursor cells in a VEGF-dependent manner as well as by upregulating expressions of VEGF, VEGFR-2 and adhesion molecules on endothelial cells. (C) 2003 Elsevier Ltd. All rights reserved.