Neurotrophins promote revascularization by local recruitment of TrkB+ endothelial cells and systemic mobilization of hematopoietic progenitors

• Published in: The Journal of clinical investigation Vol. 115; no. 3; pp. 653 - 663
• Main Authors: Kermani, Pouneh, Rafii, Dahlia, Jin, David K, Whitlock, Paul, Schaffer, Wendy, Chiang, Anne, Vincent, Loic, Friedrich, Matthias, Shido, Koji, Hackett, Neil R, Crystal, Ronald G, Rafii, Shahin, Hempstead, Barbara L
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.03.2005
• Subjects: Adenoviridae - genetics; Adenoviridae - metabolism; Animals; Biomarkers - metabolism; Brain-Derived Neurotrophic Factor - genetics; Brain-Derived Neurotrophic Factor - metabolism; Cell Line; Chemotaxis; Endothelial Cells - cytology; Endothelial Cells - physiology; Female; Genetic Vectors; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - physiology; Humans; Ischemia - metabolism; Ischemia - pathology; Male; Mice; Mice, Inbred Strains; Neovascularization, Physiologic; Nerve Growth Factors - metabolism; Rats; Receptor, trkB - metabolism; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci200522655

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.