Neurotrophins promote revascularization by local recruitment of TrkB+ endothelial cells and systemic mobilization of hematopoietic progenitors
Pouneh Kermani, … , Shahin Rafii, Barbara L. Hempstead
Pouneh Kermani, … , Shahin Rafii, Barbara L. Hempstead
Published March 1, 2005
Citation Information: J Clin Invest. 2005;115(3):653-663. https://doi.org/10.1172/JCI22655.
View: Text | PDF
Article Angiogenesis

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

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.

Authors

Pouneh Kermani, Dahlia Rafii, David K. Jin, Paul Whitlock, Wendy Schaffer, Anne Chiang, Loic Vincent, Matthias Friedrich, Koji Shido, Neil R. Hackett, Ronald G. Crystal, Shahin Rafii, Barbara L. Hempstead

×

Figure 7

Options: View larger image (or click on image) Download as PowerPoint
AdBDNF induces mobilization of hematopoietic cells. (A) Total white bloo...
AdBDNF induces mobilization of hematopoietic cells. (A) Total white blood cells (WBCs) in peripheral blood were quantified at 6 or 11 days after the injection of AdNull (yellow), AdVEGF-A (blue), or AdBDNF (red) into the tail veins of C57BL/6 mice. (B) Flow cytometry analysis of peripheral blood from animals treated with AdBDNF. CD11b+ and Sca-1+ cells are mobilized by AdBDNF. Percentages indicate percentage of positive cells detected by flow cytometry. (C) Flow cytometry analysis detected a 3.1-fold increase for Sca-1 at day 6 and 3.7 and 3.1-fold increases for Sca-1 and CD11b, respectively, 11 days after injection, in animals treated with AdBDNF. The bar graph illustrates the calculated cell number obtained by multiplying the percentage of positive cells, as measured by flow cytometry, by total WBC count. This experiment was done with 2 animals in each group treated. The numbers above the bars indicate the fold increase in WBC count. (D) Flow cytometry analysis of the peripheral blood in animals injected with AdNull (yellow), AdBDNF (red), or AdBDNF in combination with DC101 antibody (blue), 6 days after injection. Treatment with the DC101 antibody had no effect on the mobilization of Sca-1+ cells in animals treated with AdBDNF. The bar graph illustrates the calculated cell number obtained by multiplying the percentage of positive cells, as measured by flow cytometry, by total WBC count. This experiment was performed with 3 animals in each group treated.