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.
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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

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AdBDNF promotes neoangiogenesis in the mouse ear model. (A) Immunohistoc...
AdBDNF promotes neoangiogenesis in the mouse ear model. (A) Immunohistochemical analysis of expression of TrkB in a section from the base of the ear pinna of a wild-type mouse. The black arrowheads show blood vessels positive for TrkB. α-, anti-. Magnification, ×40. (B) Section from the base of the ear pinna of an untreated mouse was examined for expression of TrkB and CD31 using double-immunofluorescence microscopy. Section was incubated with biotinylated anti-CD31, followed by rhodamine-avidin, and with TrkB antisera, detected with fluorescein-conjugated secondary antibody. The white arrowhead shows the colocalization of CD31 and TrkB. C, cartilage. Magnification, ×40. (C) Whole-mount immunostaining with anti-CD31 of ear skin of mice treated with AdGFP, AdVEGF-A, or AdBDNF (n = 3/group). One week to 10 weeks after injection, ears were removed and the skin was separated from cartilage. Skin was permeablized with Triton and was incubated with antisera against CD31 for whole-mount immunohistochemistry. VIP-based immunodetection yielded a red reaction product. Magnification, ×10. (D) Quantitative analysis of the total vessel length from 4 peripheral fields of tissues obtained at 7, 10, and 14 days and 4 and 10 weeks after injection was performed by investigators, who were “blinded” to sample identity, using NIH Image. *P < 0.001. Yellow, AdGFP; blue, AdVEGF-A; red, AdBDNF.