Neurotrophins promote revascularization by local recruitment of TrkB+ endothelial cells and systemic mobilization of hematopoietic progenitors.
| Publication Type | Academic Article |
| Authors | Kermani P, Rafii D, Jin D, Whitlock P, Schaffer W, Chiang A, Vincent L, Friedrich M, Shido K, Hackett N, Crystal R, Rafii S, Hempstead B |
| Journal | J Clin Invest |
| Volume | 115 |
| Issue | 3 |
| Pagination | 653-63 |
| Date Published | 03/01/2005 |
| ISSN | 0021-9738 |
| Keywords | Brain-Derived Neurotrophic Factor, Endothelial Cells, Hematopoietic Stem Cells, Neovascularization, Physiologic, Nerve Growth Factors, Receptor, trkB |
| Abstract | 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. |
| DOI | 10.1172/JCI22655 |
| PubMed ID | 15765148 |
| PubMed Central ID | PMC1051987 |