Mechanistic insights into the functional role of vascular endothelial growth factor and its signalling partner brain‐derived neurotrophic factor in angiogenic tube formation

Abstract

The process of angiogenesis, that is, sprouting of capillaries, is well defined in terms of endothelial cell proliferation involving the ERK1/2 pathway. However, less is known about the signal transduction cascade being associated with endothelial cell migration. In the current issue of Acta Physiologica, Usui et al. (2014) provide mechanistic insights into the functional role of brain-derived neurotrophic factor (BDNF) in angiogenic tube formation. Angiogenesis is part of a variety of physiological as well as pathophysiological processes including embryonic development, wound healing, ischaemic cardiovascular diseases, cancer and neurodegenerative diseases. This tightly regulated process of blood formation involves the formation of endothelial tip cells, which navigate in response to guidance signals and adhere to the extracellular matrix to migrate. Stalk cells behind the tip cell proliferate, elongate and form a lumen to finally create a new capillary vessel (Carmeliet & Jain 2011). Vascular endothelial growth factor (VEGF) is the most potent angiogenic factor. Interestingly, VEGF is also highly involved in neurodevelopment and neurodegenerative processes by modulating neuronal migration, axon outgrowth, axon guidance and neuronal survival as recently reviewed (Carmeliet & Ruiz de Almodovar 2013). Brain-derived neurotrophic factor is one of the most active members of the neurotrophin family of growth factors in stimulating and controlling neurogenesis and is involved in neuronal survival, and the growth and differentiation of new neurones and synapses (Acheson et al. 1995, Huang & Reichardt 2001, Lessmann et al. 2003, Fritzsch et al. 2004, Skaper 2008, Lu et al. 2014). Accordingly, VEGF and BDNF are implicated in the same processes, which may be indicative of a cooperative function. Indeed, in a model of traumatic brain injury, evidence has been supplied that concomitant upregulation of VEGF and BDNF is associated with increased neuronal cell proliferation and differentiation (Wu et al. 2008). Recently, it has been shown that VEGF together with BDNF furthers brain plasticity after stroke by promoting angiogenesis (Chen et al. 2005), and Long et al. (2013) have demonstrated that VEGF and BDNF act in concert to induce capillary sprouting. However, the exact mechanisms remained unclear. First evidence that BDNF is involved in the process of angiogenesis was supplied by a study on developing embryonic myocardium showing that overexpression of BDNF is associated with an increased capillary density (Donovan et al. 2000). In further studies on brain-derived endothelial cells, it was shown that the action of BDNF, which is mainly mediated by the tropomyosin-related kinase (TrkB) receptor, results in an activation of the PI3-kinase/Akt pathway (Kim et al. 2004). Akt phosphorylation is known to promote cell migration, and indeed, it was demonstrated that the BDNF/TrkB pathway is relevant for cancer cell but also for endothelial cell migration (Hu et al. 2007, Au et al. 2009). For angiogenesis, it is well described that activation of VEGFR-2 by VEGF leads to an activation of PI3K/Akt and cell migration (Gliki et al. 2002, Chen et al. 2003) linking the BDNF and VEGF pathway. Furthermore, it has been demonstrated that activation of VEGFR-2 by VEGF results in an increased reactive oxygen species (ROS) production by gp91phox/(Nox2)-dependent NADPH oxidase (Ushio-Fukai 2007), which has likewise been linked to endothelial cell migration (Ikeda et al. 2005). In the present issue of Acta Physiologica, Usui and co-workers (Usui et al. 2014) elegantly decoded in a very well-controlled study the signal transduction cascade associated with BDNF-induced angiogenic tube formation. In an experimental set-up employing assays such as Matrigel plug and Boyden chamber, they documented that BDNF induces the signal transduction pathway TrkB -> Nox2 -> ROS -> PI3K/Akt resulting in endothelial cell migration. It has recently been shown by Chen et al. (2005) and confirmed by the data of Usui in the present issue of Acta Physiologica (Usui et al. 2014) that BDNF expression and action is dependent on the VEGFR-2 identifying BDNF as downstream signalling partner of VEGF, although, dependent on the tissue, BDNF might also influence the expression of VEGF (Katare et al. 2009). The findings that BDNF, that is, TrkB signalling, induces VEGFR-2 expression (Kim et al. 2004, Au et al. 2009) and that Nox2-derived ROS promote VEGFR-2 autophosphorylation and activation (Ushio-Fukai 2007) may explain the fact that BDNF treatment promotes angiogenic tube formation to a similar extent as VEGF does (Kermani et al. 2005). Investigating the functional role of BDNF in endothelial cell proliferation, Usui et al. (2014) demonstrated that BDNF neither induced ERK1/2 activation nor endothelial cell proliferation. These data indicate that the VEGF/BDNF/Akt pathway is exclusively responsible for cell migration, whereas the VEGF/ERK pathway accounts for cell proliferation. Together, these two pathways stimulate angiogenic tube formation (Fig. 1). Resolving the mechanisms being responsible for angiogenic tube formation in detail might be of major clinical relevance in terms of promoting (wound healing) or preventing (cancer) angiogenesis. There is no conflict of interest.