Thrombospondins deployed by thrombopoietic cells determine angiogenic switch and extent of revascularization
Thrombospondins deployed by thrombopoietic cells determine angiogenic switch and extent of revascularization
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DOI：
10.1172/jci29314
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发表时间：
2006-12-01
影响因子：
15.9
通讯作者：
Rafii, Shahin
中科院分区：
文献类型：
--
作者：
Kopp, Hans-Georg;Hooper, Andrea T.;Rafii, Shahin
血栓生成细胞可能通过释放促血管生成因子和抗血管生成因子而不同地促进或抑制组织血管生成。然而，控制造血细胞血管生成表型的分子决定因素仍不清楚。在这里，我们表明，巨核细胞和血小板表达和释放血栓反应蛋白(TSPs)是一个主要的抗血管生成开关。在后肢缺血模型中，TSP抑制血栓生成，减少骨髓抑制后的骨髓微血管重建，并限制血管重建的程度。我们证明，与WT小鼠相比，同时缺乏TSPI和TSP2的小鼠(TSP-DKO小鼠)在骨髓抑制后的血小板生成恢复显著增强。TSP-DKO小鼠的巨核细胞和血小板水平迅速恢复，从而加速了骨髓抑制和缺血后肢的血运重建。此外，来自TSP-DKO小鼠的造血细胞在支持Matrigel栓中的新血管生成方面更有效。TSP-DKO促血管生成细胞的促血管生成活性是通过激活基质细胞衍生因子-1和促进基质细胞衍生因子1的释放而实现的。因此，TSP缺陷的促血管生成细胞发挥促血管生成因子的作用，促进骨髓内血管生成和缺血后肢体的血运重建。因此，干扰TSP细胞储存的释放可能在临床上有效地增强新生血管的生成。
Thrombopoietic cells may differentially promote or inhibit tissue vascularization by releasing both pro- and antiangiogenic factors. However, the molecular determinants controlling the angiogenic phenotype of thrombopoietic cells remain unknown. Here, we show that expression and release of thrombospondins (TSPs) by megakaryocytes and platelets function as a major antiangiogenic switch. TSPs inhibited thrombopoiesis, diminished bone marrow microvascular reconstruction following myelosuppression, and limited the extent of revascularization in a model of hind limb ischemia. We demonstrate that thrombopoietic recovery following myelosuppression was significantly enhanced in mice deficient in both TSPI and TSP2 (TSP-DKO mice) in comparison with WT mice. Megakaryocyte and platelet levels in TSP-DKO mice were rapidly restored, thereby accelerating revascularization of myelosuppressed bone marrow and ischemic hind limbs. in addition, thrombopoietic cells derived from TSP-DKO mice were more effective in supporting neoangiogenesis in Matrigel plugs. The proangiogenic activity of TSP-DKO thrombopoietic cells was mediated through activation of MMP-9 and enhanced release of stromal cell-derived factor 1. Thus, TSP-deficient thrombopoietic cells function as proangiogenic agents, accelerating hemangiogenesis within the marrow and revascularization of ischemic hind limbs. As such, interference with the release of cellular stores of TSPs may be clinically effective in augmenting neoangiogenesis.