Reversal of cellular roles in angiogenesis: implications for anti-angiogenic therapy.
Reversal of cellular roles in angiogenesis: implications for anti-angiogenic therapy.
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血管生成中细胞作用的逆转：抗血管生成治疗的影响。
DOI：
10.1159/000109965
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发表时间：
2008
影响因子：
1.7
通讯作者：
Perris,Roberto
中科院分区：
文献类型：
--
作者：
Virgintino,Daniela;Ozerdem,Ugur;Girolamo,Francesco;Roncali,Luisa;Stallcup,WilliamB;Perris,Roberto
无论发生在胚胎发育期间，在病理生理条件下，如伤口愈合/组织再生，还是在完全病理条件下，如癌症和炎性疾病，血管生成传统上被认为是强烈的内皮驱动的过程。事实上，血管生成模型的主要特征，如Folkman [1]在1971年首次提出的那样，在很大程度上保留了下来，涉及内皮细胞作为小管生成过程的主要效应物[2]。如图1a所示，促血管生成生长因子（特别是VEGF）触发内皮细胞活化、增殖和运动。除了固有的内皮细胞外，循环内皮前体也可能参与相互连接的新小管的形成[3]。另一个关键作用是由局部周细胞或骨髓来源的周细胞祖细胞发挥[4-6]。根据血管生成法则，周细胞被迁移的内皮细胞募集以赋予新生血管结构稳定性[2，4-7]。事实上，通过NG 2蛋白聚糖[8]或PDGFRβ [5，6]靶向周细胞强烈影响新生血管发生，也可能影响淋巴管生成。我们最近的观察表明，在周细胞靶向范例中观察到的血管化水平降低是由于传统模型中内皮细胞和周细胞的作用逆转（图1a）。在胎儿人脑（图1b-d）[8]、鼠肿瘤模型（图1 e-g）[9]、皮下基质胶塞试验和成年小鼠角膜[7]中的正常血管生成过程中，在发芽前沿观察到仅由周细胞组成的索状结构（另见在线补充图S1; www. karger。com/doi/10.1159/000109965）。这些索似乎作为引导结构，用于内皮细胞的渐进性侵入以构建成熟血管（另见补充视频1; www. karger。com/doi/10.1159/000109965）。
Whether occurring during embryonic development, in pathophysiological conditions, such as wound healing/tissue regeneration, or in fully pathological conditions, such as cancer and inflammatory diseases, angiogenesis is traditionally thought to be a strongly endotheliumdriven process. In fact, the main features of the angiogenic model, largely preserved as first proposed by Folkman [1] in 1971, implicate endothelial cells as primary effectors of the tubulogenesis process [2]. As depicted in figure 1a, pro-angiogenic growth factors (especially VEGF) trigger endothelial cell activation, proliferation and motility. In addition to resident endothelial cells, circulating endothelial precursors may also participate in the formation of interconnected neotubules [3]. Another crucial role is played by local pericytes or bone marrow-derived pericyte progenitors [4-6]. According to the angiogenesis dogma, pericytes are recruited by migrating endothelial cells to confer stability to nascent vascular structures [2, 4-7]. Indeed, targeting pericytes through NG2 proteoglycan [8] or PDGFRβ [5, 6] strongly impacts neovasculogenesis and may also affect lymphangiogenesis.Our recent observations suggest that the reduced levels of vascularization observed in pericyte targeting paradigms are due to a reversal of the roles proposed for endothelial and pericytic cells in the traditional model (fig. 1a). During normal angiogenesis in fetal human brain (fig. 1b-d)[8], in murine tumor models (fig. 1e-g)[9], in subcutaneous Matrigel plug assays and in adult mouse cornea [7], cord-like structures composed solely of pericytes are observed at the sprouting front (see also online suppl. fig. S1; www. karger. com/doi/10.1159/000109965). These cords appear to serve as guiding structures for the progressive invasion of endothelial cells to construct the mature vessel (see also suppl. video 1; www. karger. com/doi/10.1159/000109965).