Thrombopoietin gene transfer-mediated enhancement of angiogenic responses to acute ischemia
Thrombopoietin gene transfer-mediated enhancement of angiogenic responses to acute ischemia
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DOI：
10.1161/01.res.0000179534.17668.f8
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发表时间：
2005-08-19
影响因子：
20.1
通讯作者：
Crystal, RG
中科院分区：
文献类型：
--
作者：
Amano, H;Hackett, NR;Crystal, RG
新血管的形成是一个复杂的过程，可能需要多种血管生成介质的协同作用。这项研究的重点是近端血管生成反应使用血小板作为一个复杂的载体的关键介质的血管生成。血小板水平由血小板生成素（TPO）的循环水平控制，血小板生成素（TPO）的功能是通过c-mpl受体激活巨核细胞分化和血小板释放。我们假设TPO基因转移通过增加血小板水平和血小板衍生的血管生成介质来增强实验性缺血的纠正。为了评估这一假设，我们使用野生型、TPO-/-和c-mpl（-/-）小鼠的急性后肢缺血模型，剖析了TPO-c-mpl巨核细胞-血小板通路在血管生成反应中的作用。数据表明，输注血小板将增强野生型小鼠的血管生成反应，而TPO-/-和c-mpl（-/-）小鼠的内源性血管生成反应减弱。与这一观察结果一致，腺病毒（Ad）介导的TPO（AdTPO）转移增强了野生型和TPO-/-，但不是c-mpl（-/-），小鼠缺血的纠正。AdTPO的局部与全身给药表明TPO基因转移的效果是全身性的，而不是局部的，并且它可以被VEGF的基因转移所取代，VEGF是血小板携带的血管生成的许多介质之一，即使在TPO-c-mpl-巨核细胞血小板途径中没有组分。
The development of new blood vessels is a complex process, likely requiring the synergy of multiple angiogenic mediators. This study focuses on the proximal angiogenic response using the platelet as a complex carrier of critical mediators of angiogenesis. Platelet levels are controlled by circulating levels of thrombopoietin (TPO) functioning to activate megakaryocyte differentiation and platelet release through the c-mpl receptor. We hypothesized that TPO gene transfer should enhance correction of experimental ischemia by providing increased levels of platelets and hence platelet-derived mediators of angiogenesis. To evaluate this hypothesis, we dissected the role of the TPO-c-mpl megakaryocyte-platelet pathway in the angiogenic response using a model of acute hindlimb ischemia of wild-type, TPO-/-, and c-mpl(-/-) mice. The data demonstrate that infusion of platelets will enhance the angiogenic response in wild-type mice and that the endogenous angiogenic response is blunted in TPO-/- and c-mpl(-/-) mice. Consistent with this observation, adenovirus (Ad)-mediated transfer of TPO (AdTPO) enhanced the correction of ischemia in wild-type and TPO-/-, but not c-mpl(-/-), mice. Local versus systemic administration of AdTPO showed that the effect of TPO gene transfer was systemic, not local, and it could be replaced by gene transfer of VEGF, one of the many mediators of angiogenesis carried by the platelets, even in the absence of components in the TPO-c-mpl-megakaryocyte platelet pathway.