Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy
Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy
复制标题
DOI：
10.1093/emboj/21.8.1939
复制
发表时间：
2002-04-15
期刊：
影响因子：
11.4
通讯作者：
Keshet, E
中科院分区：
文献类型：
--
作者：
Dor, Y;Djonov, V;Keshet, E
为了深入了解成人器官的新血管形成并揭示基于血管内皮生长因子（VEGF）的治疗性血管生成中的固有障碍，设计了用于VEGF表达的条件转换的转基因系统。该系统允许以任何选定的时间表在心肌或肝脏中特异性地可逆诱导VEGF，从而避免由于VEGF的发育错误表达导致的胚胎致死。使用这个系统，我们展示了一个渐进的，无限的分歧现有的脉管系统。然而，在缺乏空间线索的情况下，产生了异常的血管树，这是与现有网络的混乱连接和形成不规则形状的囊状血管的结果。VEGF还引起了大量的和高度破坏性的水肿。重要的是，VEGF刺激的过早停止导致大多数获得性血管的消退，从而挑战依赖于短刺激持续时间的治疗方法的效用。定义了一个临界转变点，超过该点，在撤回VEGF后重塑的新血管持续数月，从而赋予器官灌注的长期改善。因此，这种新的遗传系统突出了在实施促血管生成治疗中存在的问题。
To gain insight into neovascularization of adult organs and to uncover inherent obstacles in vascular endothelial growth factor (VEGF)-based therapeutic angiogenesis, a transgenic system for conditional switching of VEGF expression was devised. The system allows for a reversible induction of VEGF specifically in the heart muscle or liver at any selected schedule, thereby circumventing embryonic lethality due to developmental misexpression of VEGF. Using this system, we demonstrate a progressive, unlimited ramification of the existing vasculature. In the absence of spatial cues, however, abnormal vascular trees were produced, a consequence of chaotic connections with the existing network and formation of irregularly shaped sac-like vessels. VEGF also caused a massive and highly disruptive edema. Importantly, premature cessation of the VEGF stimulus led to regression of most acquired vessels, thus challenging the utility of therapeutic approaches relying on short stimulus duration. A critical transition point was defined beyond which remodeled new vessels persisted for months after withdrawing VEGF, conferring a long-term improvement in organ perfusion. This novel genetic system thus highlights remaining problems in the implementation of pro-angiogenic therapy.