VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogenous PDGF-B-PDGFRβ signaling
VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogenous PDGF-B-PDGFRβ signaling
复制标题
DOI：
10.1242/jcs.02483
复制
发表时间：
2005-08-15
影响因子：
4
通讯作者：
Miyazawa, K
中科院分区：
文献类型：
--
作者：
Kano, MR;Morishita, Y;Miyazawa, K
与VEGF-A，FGF-2，或PDGF-BB的组合刺激已成为一种有效的治疗性血管生成的策略，虽然这些因素的协同作用的机制还没有得到很好的理解。在本研究中，我们研究了VEGF-A和FGF-2之间的协同作用的机制，通过使用Matrigel plug法在体内和胚胎干细胞（ESC）衍生的VEGF受体2（VEGFR 2）阳性细胞在体外。体外实验表明，除了具有直接的促有丝分裂作用外，这些分子以细胞类型特异性方式增强细胞间PDGF-B信号传导：VEGF-A增强内皮PDGF-B表达，而FGF-2增强壁PDGF受体P（PDGFR，6）表达。与单一药物刺激相比，VEGF-A和FGF-2的共刺激在体外引起显著的壁细胞募集，在体内形成功能性新血管。这些作用不仅被抗PDGFR β中和抗体消除，而且被外源性PDGF-BB消除，其可以压倒内源性PDGF-BB分布。这些发现表明了保护内皮周围PDGF-BB梯度的重要性。因此，我们证明了内源性PDGF-B-PDGFR β信号传导的定向增强对于VEGF-A和FGF-2对成人新血管生成的协同作用是不可或缺的。这些发现为深入了解生长因子共刺激效应的机制提供了依据，这可能会导致合理设计治疗性血管生成策略。
Combined stimulation with VEGF-A, FGF-2, or PDGF-BB has emerged as a potent strategy for therapeutic angiogenesis, although the mechanisms underlying the synergism of these factors are not well understood. In the present study, we investigated the mechanism of synergism between VEGF-A and FGF-2 by using Matrigel plug assay in vivo and embryonic stem cell (ESC)-derived VEGF receptor 2 (VEGFR2)-positive cells in vitro. Experiments in vitro revealed that, in addition to having direct mitogenic effects, these molecules enhance intercellular PDGF-B signaling in a cell-type specific manner: VEGF-A enhances endothelial PDGF-B expression, whereas FGF-2 enhances mural PDGF receptor P (PDGFR,6) expression. Co-stimulation with VEGF-A and FGF-2 caused significant mural cell recruitment in vitro and formation of functional neovasculature in vivo, compared with single-agent stimulation. These effects were abrogated not only by anti-PDGFR beta neutralizing antibody, but also by exogenous; PDGF-BB, which could overwhelm the endogenous PDGF-BB distribution. These findings indicated the importance of preservation of the periendothelial PDGF-BB gradient. Thus, we demonstrated that the directional enhancement of endogenous PDGF-B-PDGFR beta signaling is indispensable for the synergistic effect of VEGF-A and FGF-2 on neoangiogenesis in adults. The findings provide insights into the mechanisms underlying the effects of co-stimulation by growth factors, which could lead to rational design of therapeutic angiogenic strategies.