Paradoxical Effects of PDGF-BB Overexpression in Endothelial Cells on Engineered Blood Vessels In Vivo
Paradoxical Effects of PDGF-BB Overexpression in Endothelial Cells on Engineered Blood Vessels In Vivo
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DOI：
10.2353/ajpath.2009.080887
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发表时间：
2009-07-01
影响因子：
6
通讯作者：
Jain, Rakesh K.
中科院分区：
文献类型：
--
作者：
Au, Patrick;Tam, Joshua;Jain, Rakesh K.
外源性血管生成因子或血管细胞的治疗性血管重建术尚未在临床上显示出疗效。注射血管生成生长因子通常会产生不稳定和异常的血管。由于血管周围细胞募集不足，移植内皮细胞所形成的血管网络仅维持一过性。我们假设，这两种方法的结合可能会产生协同作用，产生更好的结果。为了促进血管周围细胞的募集，对人脐静脉内皮细胞进行了基因修饰，以过表达血小板衍生生长因子(PDGF)-BB。PDGF-BB过表达可促进血管周围前体细胞(10T1/2细胞)在体外的增殖和迁移。当模拟感染的内皮细胞单独植入体内时，它们形成了短暂的血管网络，并在第30天退化。PDGF-BB过表达可增强体内血管内皮细胞的存活。然而，表达PDGF-BB的血管网络未能建立开放的血流。矛盾的是，PDGF-BB高表达的内皮细胞与10T1/2细胞共植入后，体内的血管网络迅速退化。PDGF-BB刺激10T1/2细胞趋化因子(C-C基序)配体2(CCL2)和CCL7的表达，导致巨噬细胞在体内聚集增加。这些结果表明血管生成生长因子和血管细胞之间存在潜在的负相互作用；它们的联合使用应该在体内仔细测试这种相反的作用。(Am J Pathol2009175：294-302；DOI：10.2353/ajpath.2009.080887)
Therapeutic revascularization with either exogenous angiogenic growth factors or vascular cells has yet to demonstrate efficacy in the clinic. Injection of angiogenic growth factors often produces unstable and abnormal blood vessels. Blood vascular networks derived from implanted endothelial cells persist only transiently due to the insufficient recruitment of perivascular cells. We hypothesize that a combination of the two approaches may act synergistically to yield a better result. To enhance the recruitment of perivascular cells, human umbilical vein endothelial cells were genetically modified to overexpress platelet-derived growth factor (PDGF)-BB. PDGF-BB overexpression promoted both proliferation and migration of perivascular precursor cells (10T1/2 cells) in vitro. When mock-infected endothelial cells were implanted alone in vivo, they formed transient blood vascular networks that regressed by day 30. PDGF-BB overexpression enhanced the survival of endothelial cells in vivo. However, the PDGF-BB-expressing vessel network failed to establish patent blood flow. Co-implantation of PDGF-BB-overexpressing endothelial cells with 10T1/2 cells paradoxically resulted in the rapid regression of the vascular networks in vivo. PDGF-BB stimulated the expression of both chemokine (C-C motif) ligand 2 (CCL2) and CCL7 in 10T1/2 cells and led to the increased accumulation of macrophages in vivo. These results suggest a potential negative interaction between angiogenic growth factors and vascular cells; their use in combination should be carefully tested in vivo for such opposing effects. (Am J Pathol 2009, 175:294-302; DOI: 10.2353/ajpath.2009.080887)