Metheny-Barlow Linda J, Tian Song, Hayes Andrew J, Li Lu-Yuan
Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA.
Microvasc Res. 2004 Nov;68(3):221-30. doi: 10.1016/j.mvr.2004.08.005.
Angiopoietin-1 (Ang1) and its receptor, Tie2, play an important role in angiogenesis and vessel maturation. We previously reported that overexpression of Ang1 in MCF7 xenograft tumors facilitated vessel stabilization by mural cells, and that cultured SMC express Tie2. Here, we investigated whether Ang1 directly acts as a chemoattractant on mural cells or their precursors. In a Matrigel plug assay, neither Ang1 nor VEGF alone induced angiogenesis but together stimulated infiltration of non-endothelial cells that were CD31-negative, vimentin-positive and also positive for VEGFR-1 and Tie2. While negative for smooth muscle actin, reactivity for desmin suggests that the cells are mural cell precursors. VEGF treatment of cultured smooth muscle cells (SMC) upregulated Tie2 and allowed for Ang1-mediated phosphorylation of Tie2 and the AKT serine-threonine kinase. The combination of Ang1 and VEGF stimulated SMC migration in a Boyden chamber-type assay. In the presence of VEGF, Tie2 is upregulated on mural cells, allowing for a migratory response to Ang1. These findings support the view that Ang1, in concert with VEGF, can act directly on mural cells or their precursors to facilitate their recruitment to new blood vessels. This action may play an important role in vascular stabilization.
血管生成素-1（Ang1）及其受体Tie2在血管生成和血管成熟过程中发挥着重要作用。我们之前报道过，在MCF7异种移植瘤中Ang1的过表达促进了壁细胞对血管的稳定作用，并且培养的平滑肌细胞（SMC）表达Tie2。在此，我们研究了Ang1是否直接作为一种趋化因子作用于壁细胞或其前体细胞。在基质胶栓实验中，单独的Ang1或VEGF均未诱导血管生成，但二者共同作用可刺激非内皮细胞浸润，这些细胞CD31阴性、波形蛋白阳性，且VEGFR-1和Tie2也呈阳性。虽然这些细胞平滑肌肌动蛋白阴性，但结蛋白反应阳性表明它们是壁细胞前体细胞。用VEGF处理培养的平滑肌细胞（SMC）会上调Tie2，并使Tie2和AKT丝氨酸 - 苏氨酸激酶发生Ang1介导的磷酸化。在Boyden小室实验中，Ang1和VEGF的组合刺激了SMC迁移。在有VEGF存在的情况下，壁细胞上的Tie2上调，从而使其对Ang1产生迁移反应。这些发现支持了以下观点：Ang1与VEGF协同作用，可直接作用于壁细胞或其前体细胞，促进它们被招募到新生血管中。这一作用可能在血管稳定过程中发挥重要作用。
