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

Abstract

Vascular endothelial growth factor-B (VEGF-B), when initially discovered, was thought to be an angiogenic factor, due to its intimate sequence homology and receptor binding similarity to the prototype angiogenic factor, vascular endothelial growth factor-A (VEGF-A). Studies demonstrated that VEGF-B, unlike VEGF-A, did not play a significant role in angiogenesis or vascular permeability and has become an active area of interest because of its role as a survival factor in pathological processes in a multitude of systems, including the brain. By characterization of important downstream targets of VEGF-B that regulate different cellular processes in the nervous system and cardiovascular system, it may be possible to develop more effective clinical interventions in diseases such as Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and ischemic heart disease, which all share mitochondrial dysfunction as part of the disease. Here we summarize what is currently known about the mechanism of action of VEGF-B in pathological processes. We explore its potential as a homeostatic protective factor that improves mitochondrial function in the setting of cardiovascular and neurological disease, with a specific focus on dopaminergic neurons in Parkinson's disease.

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.