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Pleiotropy of tissue-specific growth factors: from neurons to vessels via the bone marrow
Dan G. Duda and Rakesh K. Jain
Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Address correspondence to: Rakesh K. Jain, Edwin L. Steele Laboratory, Department of Radiation Oncology, 100 Blossom Street, Boston, Massachusetts 02114, USA. Phone: (617) 726-4083; Fax: (617) 724-1819; E-mail: jain@steele.mgh.harvard.edu.
Find articles by Duda, D. in: JCI | PubMed | Google Scholar
Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Address correspondence to: Rakesh K. Jain, Edwin L. Steele Laboratory, Department of Radiation Oncology, 100 Blossom Street, Boston, Massachusetts 02114, USA. Phone: (617) 726-4083; Fax: (617) 724-1819; E-mail: jain@steele.mgh.harvard.edu.
Find articles by Jain, R. in: JCI | PubMed | Google Scholar
Published March 1, 2005 - More info
J Clin Invest. 2005;115(3):596–598. https://doi.org/10.1172/JCI24511.
© 2005 The American Society for Clinical Investigation
Growth factors that were once considered tissue specific can have unexpectedly broad effects. For example, signals from endothelial growth factors govern not only tissue neovascularization, but also the development and function of different organs such as the pancreas (1), liver (2), fat (3), and hematopoietic tissues (4). Similarly complex relationships have been found in the nervous system (5). VEGF (also known as VEGF-A) is a critical factor in angiogenesis during development and disease (6); nonetheless, it has recently been shown to be neuroprotective in a rat model of amyotrophic lateral sclerosis (a neurodegenerative disease causing a progressive loss of motor neurons). This finding provides an unexpected new therapeutic platform for the treatment of this debilitating disease (7). Some elegant work in mutant mouse models has also demonstrated that factors such as brain-derived neurotrophic factor (BDNF; ref. 8) and receptors involved in axon guidance (9) play a crucial role in neovascularization during embryonic development.
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Neurotrophic factors promote adult neovascularization
In this issue of the JCI, Kermani et al. (10) describe, we believe for the first time, the effects of BDNF and neurotrophin-4 (NT-4) on neovascularization in adult mice. The proangiogenic effects of these hypoxia-responsive neurotrophic factors are comparable to those of VEGF but are independent of the VEGF receptor 2 pathway. In part, these effects are exerted directly through the cognate receptor for the neurotrophic factors, BDNF receptor tyrosine kinase (TrkB) that is expressed on subsets of endothelial cells. More strikingly, the authors show that BDNF is similar to other angiogenic factors — such as VEGF, angiopoietin 1 (Ang1), and placenta-derived growth factor (PlGF) (4, 11) — in its ability to affect the hematopoietic system by mobilizing precursor cells (Figure 1). Recruitment of these precursor cells promoted neovascularization (Figure 2) and alleviated limb ischemia.
Figure 1The functional pleiotropy of BDNF extends beyond the nervous system. BDNF, similar to NT-4, exerts its complex signaling effects via TrkB that is present on neurons. These effects include the modulation of neuronal differentiation, survival, and function. In this issue of the JCI, Kermani et al. (10) report a more complex role for this neurotrophic factor: BDNF can mobilize TrkB+ hematopoietic precursor cells (HPCs) for both hematopoiesis and tissue neovascularization. In addition, BDNF can promote angiogenesis by directly interacting with TrkB expressed on ECs.
Figure 2Cellular and molecular mechanisms of BDNF-induced neovascularization. BDNF was recently implicated in new vessel formation, in both mouse embryos (8) and adult mice (10). In adults, the formation of new vessels in response to BDNF overexpression is the result of both direct effects on TrkB expressed by tissue-resident ECs and the recruitment of TrkB+VEGFR2+CD11b+Sca1+ myeloid HPCs. The latter cells may indirectly promote neovascularization by releasing various factors, including Ang2 and MMPs. Nevertheless, a direct involvement of myeloid HPCs in vessel formation cannot be excluded, as they also have the potential to acquire an EC or mural cell (MC) phenotype.
This work establishes that neurotrophins are novel proangiogenic factors. The authors report (10) that BDNF does not induce the recruitment of pericytes to blood vessels (an important step in the stabilization and maturation of new vasculature), but rather promotes the recruitment of myeloid progenitor cells of unknown function. These findings warrant further investigation of the role and therapeutic potential of these factors in the treatment of diseases ranging from cancer to cardiac ischemia. Moreover, they describe yet another facet of the intricate relationship between hematopoietic cells and tissue neovascularization. Understanding the molecular and cellular underpinnings of this interaction may prove to be crucial for both regenerative medicine and cancer therapy.
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