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

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

Research output: Contribution to journalArticle

172 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)653-663
Number of pages11
JournalJournal of Clinical Investigation
Volume115
Issue number3
DOIs
Publication statusPublished - 1 Mar 2005
Externally publishedYes

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Brain-Derived Neurotrophic Factor
Nerve Growth Factors
Phosphotransferases
Endothelial Cells
Vascular Endothelial Growth Factor A
Extremities
Bone Marrow
Hindlimb
Embryonic Development
Ear
Skeletal Muscle
Ischemia
Maintenance
Ligands

ASJC Scopus subject areas

  • Medicine(all)

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Neurotrophins promote revascularization by local recruitment of TrkB + endothelial cells and systemic mobilization of hematopoietic progenitors. / Kermani, Pouneh; Rafii, Dahlia; Jin, David K.; Whitlock, Paul; Schaffer, Wendy; Chiang, Anne; Vincent, Loic; Friedrich, Matthias; Shido, Koji; Hackett, Neil R.; Crystal, Ronald; Rafii, Shahin; Hempstead, Barbara L.

In: Journal of Clinical Investigation, Vol. 115, No. 3, 01.03.2005, p. 653-663.

Research output: Contribution to journalArticle

Kermani, P, Rafii, D, Jin, DK, Whitlock, P, Schaffer, W, Chiang, A, Vincent, L, Friedrich, M, Shido, K, Hackett, NR, Crystal, R, Rafii, S & Hempstead, BL 2005, 'Neurotrophins promote revascularization by local recruitment of TrkB + endothelial cells and systemic mobilization of hematopoietic progenitors', Journal of Clinical Investigation, vol. 115, no. 3, pp. 653-663. https://doi.org/10.1172/JCI200522655
Kermani, Pouneh ; Rafii, Dahlia ; Jin, David K. ; Whitlock, Paul ; Schaffer, Wendy ; Chiang, Anne ; Vincent, Loic ; Friedrich, Matthias ; Shido, Koji ; Hackett, Neil R. ; Crystal, Ronald ; Rafii, Shahin ; Hempstead, Barbara L. / Neurotrophins promote revascularization by local recruitment of TrkB + endothelial cells and systemic mobilization of hematopoietic progenitors. In: Journal of Clinical Investigation. 2005 ; Vol. 115, No. 3. pp. 653-663.
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AU - Rafii, Dahlia

AU - Jin, David K.

AU - Whitlock, Paul

AU - Schaffer, Wendy

AU - Chiang, Anne

AU - Vincent, Loic

AU - Friedrich, Matthias

AU - Shido, Koji

AU - Hackett, Neil R.

AU - Crystal, Ronald

AU - Rafii, Shahin

AU - Hempstead, Barbara L.

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