Neurotrophins promote revascularization by local recruitment of TrkB+ endothelial cells and systemic mobilization of hematopoietic progenitors.
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.
Kermani
Pouneh
P
Division of Hematology, Weill Medical College of Cornell University, New York, New York 10021, USA.
Rafii
Dahlia
D
Jin
David K
DK
Whitlock
Paul
P
Schaffer
Wendy
W
Chiang
Anne
A
Vincent
Loic
L
Friedrich
Matthias
M
Shido
Koji
K
Hackett
Neil R
NR
Crystal
Ronald G
RG
Rafii
Shahin
S
Hempstead
Barbara L
BL
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002633:Chemotaxis; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D005260:Female; D005822:Genetic Vectors; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018919:Neovascularization, Physiologic; D009414:Nerve Growth Factors / Q000378:metabolism*; D051381:Rats; D020813:Receptor, trkB / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D020813:Receptor, trkB; D040301:Vascular Endothelial Growth Factor Receptor-2; C073922:neurotrophin 4