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.

Stroke-Evoked Angiogenesis Results in a Transient Population of Microvessels

“…Furthermore, recent studies with VEGF antagonists point to a continuing vascular dependence on VEGF in normal adult peripheral capillaries and in the choroid plexus (Baffert et al, 2006;Kamba et al, 2006). In addition to a postulated vessel-stabilizing role for VEGF (Maharaj et al, 2006), vessel stabilization can also be dependent on neurotrophin signaling, as was recently showed in ischemic skeletal muscle (Kermani et al, 2005). The vascular regression observed in the present study, then, may reflect a coordinated reduction in these or other vessel stabilizing molecules.…”

“…Thus, the discrepancy between the present work and this previous study might stem from the use of different species or from methodological differences in vessel labeling and quantitation or both. Recent studies suggest that angiogenesis triggered by exogenous VEGF or by ischemia in peripheral vascular beds requires additional factors for longterm stabilization (Kermani et al, 2005;Pettersson et al, 2000). The regression of supernumerary vessels in the infarcted tissue seen in the present study at the longer survivals of 90 and 165 days may reflect the well-documented downregulation of ischemictriggered expression of VEGF (Hayashi et al, 2003) in the brain 1 week after stroke.…”

Brain-Derived Neurotrophic Factor: A Newly Described Mediator of Angiogenesis

“…Given the critical role of BDNF in perinatal vessel stabilization and continued expression of TrkB in the adult vasculature we have investigated direct angiogenic actions of exogenous delivery of BDNF in normal and ischemic conditions in the adult mouse (Kermani et al 2005). In a femoral artery ligation model, BDNF protein is significantly induced in ischemic, as compared to non-ischemic tissue.…”

Progress and prospects: Cell based regenerative therapy for cardiovascular disease

“…28 Yet another potential mechanism involves a brain-derived neurotrophic factor (BNDF) that has been shown to promote neovascularization by simultaneously attracting a subpopulation of local endothelial cells that express the BNDF receptor, and recruiting hematopoietic progenitors from the bone marrow to ischemic skeletal muscle. 29 Finally, the mechanical effects of cell transfer (i.e. strengthening of the scar by the presence of a new tissue mass) may but itself favorably alter LV geometry and improve cardiac function.…”