Insights into the Mechanisms Involved in Protective Effects of VEGF-B in Dopaminergic Neurons

Figure 1

Proposed mechanisms of VEGF-B’s protective effects in dopaminergic neurons. Black solid lines indicate pathways previously shown for DA cells. Black dashed lines indicate hypothesized pathways, based on other cell types. Blue lines indicate a possible feedback loop between VEGF-B and PGC-1α. Arrowheads and + signs: activation, − signs: inhibition. LCFA: long chain fatty acids; FA: fatty acids. In neuron survival, VEGF-B via VEGFR-1 upregulates pAkt and to a lesser extent pErk. Given data seen in cardiac tissue and sensory neurons, we propose that mTOR is increased downstream and generates antiapoptotic effects via upregulation of PEDF. Previous data also shows that VEGF-B mediated upregulation of fatty acid transporters FATP1 and FATP4 via VEGFR-1, leading to LCFA uptake and increasing mitochondrial function. This could generate more ATP and decreases ROS, promoting neuronal protection. Additionally, given VEGF-B action on pAMPK in cardiac cell protection, reduced AMPK phosphorylation may be involved in neuroprotection and serves as another way of improving mitochondrial function during neuron injury. The nuclear respiratory factors, NRF1 and NRF2, are downstream of PGC-1α in neuroprotection, and given findings in skeletal muscle, VEGF-B may be regulated by PGC-1α, via NRF1 and NRF2. Applying data from prior work in cardiac cells, we also suggest that VEGF-B may increase PGC-1α expression, providing an autocrine feedback loop in which either VEGF-B is directly upregulating PGC-1α followed by increased mitochondrial activity or VEGF-B could be increasing mitochondrial activity that is then feeding back to increase PGC-1α in order to maintain increased ATP production.