Neurotrophins promote revascularization by local recruitment of TrkB+ endothelial cells and systemic mobilization of hematopoietic progenitors
Neurotrophins promote revascularization by local recruitment of TrkB+ endothelial cells and systemic mobilization of hematopoietic progenitors
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DOI：
10.1172/jci200522655
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发表时间：
2005-03-01
影响因子：
15.9
通讯作者：
Hempstead, BL
中科院分区：
文献类型：
--
作者：
Kermani, P;Rafii, D;Hempstead, BL
神经营养因子脑源性神经营养因子（BDNF）是胚胎发育期间通过对表达原溶酶受体激酶B（Trk B）的内皮细胞的直接血管生成作用来维持心脏血管壁稳定性所必需的。然而，BDNF和相关的神经营养因子配体，神经营养因子-4（NT-4），在成人组织血管再生的调节中的作用是未知的。为了研究BDNF在介导缺血和非缺血性成年小鼠组织的新血管形成中的潜在血管生成能力，我们利用后肢缺血和皮下Matrigel模型。BDNF和NT-4对内皮细胞的募集和对基质胶栓内通道形成的促进作用与VEGF-A诱导的相当。将BDNF引入非缺血性耳朵或缺血性肢体诱导新生血管形成，毛细血管密度增加2倍。值得注意的是，BDNF治疗在21天内逐渐增加了缺血肢体的血流量，与VEGF-A治疗相似。BDNF增强毛细血管形成的机制部分是通过TrkB受体的局部激活以及Sca-1（+）CD 11b（+）促血管生成造血细胞的募集介导的。BDNF诱导对共表达TrkB的骨髓源性Sca-1（+）造血细胞亚群的有效直接化学动力学作用。这些研究表明，BDNF的局部区域递送可能提供一种新的机制，通过直接作用于骨骼肌中表达TrkB的局部内皮细胞和募集特定的TrkB（+）骨髓源性造血细胞亚群来为新形成的血管提供内皮周围支持，从而诱导新血管生成。
The neurotrophin brain-derived neurotrophic factor (BDNF) is required for the maintenance of cardiac vessel wall stability during embryonic development through direct angiogenic actions on endothelial cells expressing the tropomysin receptor kinase B (TrkB). However, the role of BDNF and a related neurotrophin ligand, neurotrophin-4 (NT-4), in the regulation of revascularization of the adult tissues is unknown. To study the potential angiogenic capacity of BDNF in mediating the neovascularization of ischemic and non-ischemic adult mouse tissues, we utilized a hindlimb ischemia and a subcutaneous Matrigel model. Recruitment of endothelial cells and promotion of channel formation within the Matrigel plug by BDNF and NT-4 was comparable to that induced by VEGF-A. The introduction of BDNF into non-ischemic ears or ischemic limbs induced neoangiogenesis, with a 2-fold increase in the capillary density. Remarkably, treatment with BDNF progressively increased blood flow in the ischemic limb over 21 days, similar to treatment with VEGF-A. The mechanism by which BDNF enhances capillary formation is mediated in part through local activation of the TrkB receptor and also by recruitment of Sca-1(+)CD11b(+) pro-angiogenic hematopoietic cells. BDNF induces a potent direct chemokinetic action on subsets of marrow-derived Sca-1(+) hematopoietic cells co-expressing TrkB. These studies suggest that local regional delivery of BDNF may provide a novel mechanism for inducing neoangiogenesis through both direct actions on local TrkB-expressing endothelial cells in skeletal muscle and recruitment of specific subsets of TrkB(+) bone marrow-derived hematopoietic cells to provide peri-endothelial support for the newly formed vessels.