Pleiotropy of tissue-specific growth factors: from neurons to vessels via the bone marrow

Abstract

Recent evidence has demonstrated that endothelial-specific growth factors affect the development of apparently unrelated organs and cells. Expanding this evidence further, new findings in this issue of the JCI show that neurotrophic factors can affect neovascularization. Neurotrophic factors achieve proangiogenic effects not only by directly affecting endothelial cells, but also by recruiting hematopoietic precursors. Further understanding of the biology of angiogenic factors, as well as of the function of hematopoietic cells in tissue neovascularization, will lead to improved therapeutic strategies for the treatment of diseases ranging from ischemia to cancer.

Figure 1

The 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 2

Cellular 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.