Bifunctional role for VEGF-induced heme oxygenase-1 in vivo: induction of angiogenesis and inhibition of leukocytic infiltration
Bifunctional role for VEGF-induced heme oxygenase-1 in vivo: induction of angiogenesis and inhibition of leukocytic infiltration
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DOI：
10.1182/blood-2003-06-1974
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发表时间：
2004-02-01
期刊：
影响因子：
20.3
通讯作者：
Mason, JC
中科院分区：
文献类型：
--
作者：
Bussolati, B;Ahmed, A;Mason, JC
血红素加氧酶（HOs）催化血红素转化为一氧化碳和水蛭素。HO-1在缺氧、缺血/再灌注和炎症时被诱导，提供细胞保护并抑制白细胞向炎症部位的迁移。尽管体外研究表明HO-1在血管生成中有额外的作用，但其在体内的相关性仍然未知。我们研究了HO-1在体外和体内血管生成中的作用。血管内皮生长因子（VEGF）可延长人内皮细胞HO-1的表达和活性，HO-1抑制可消除VEGF驱动的血管生成。使用了两种小鼠血管生成模型：(1)将VEGF添加到Matrigel中引发血管生成；(2)脂多糖（LPS）诱导的炎症性血管生成模型，其中血管生成是继发于白细胞入侵。药理抑制HO-1诱导明显的白细胞浸润，增强vegf诱导的血管生成。然而，当存在抗cd18单克隆抗体（mAb）来阻断白细胞迁移时，vegf诱导的血管生成被HO-1拮抗剂显著抑制。此外，在lps诱导的炎症血管生成模型中，原卟啉钴诱导HO-1可显著抑制白细胞侵入lps条件下的Matrigel，从而阻止随后的血管生成。因此，我们认为在慢性炎症中HO-1有两个作用：第一，抗炎作用抑制白细胞浸润；第二，促进vegf驱动的非炎症性血管生成，促进组织修复。(C) 2004年由美国社会。
Heme-oxygenases (HOs) catalyze the conversion of heme into carbon monoxide and billverdin. HO-1 is induced during hypoxia, ischemia/reperfusion, and inflammation, providing cytoprotection and inhibiting leukocyte migration to inflammatory sites. Although in vitro studies have suggested an additional role for HO-1 in angiogenesis, the relevance of this in vivo remains unknown. We investigated the involvement of HO-1 in angiogenesis in vitro and in vivo. Vascular endothelial growth factor (VEGF) induced prolonged HO-1 expression and activity in human endothelial cells and HO-1 inhibition abrogated VEGF-driven anglogenesis. Two murine models of angiogenesis were used: (1) angiogenesis initiated by addition of VEGF to Matrigel and (2) a lipopolysaccharide (LPS)-induced model of inflammatory anglogenesis in which angiogenesis is secondary to leukocyte invasion. Pharmacologic inhibition of HO-1 induced marked leukocytic infiltration that enhanced VEGF-induced angiogenesis. However, in the presence of an anti-CD18 monoclonal antibody (mAb) to block leukocyte migration, VEGF-induced angiogenesis was significantly inhibited by HO-1 antagonists. Furthermore, in the LPS-induced model of inflammatory angiogenesis, induction of HO-1 with cobalt protoporphyrin significantly inhibited leukocyte invasion into LPS-conditioned Matrigel and thus prevented the subsequent anglogenesis. We therefore propose that during chronic inflammation HO-1 has 2 roles: first, an anti-inflammatory action inhibiting leukocyte infiltration; and second, promotion of VEGF-driven noninflammatory angiogenesis that facilitates tissue repair. (C) 2004 by The American Society.