VEGF ligands and receptors: implications in neurodevelopment and neurodegeneration

Abstract

Intensive research in the last decade shows that the prototypic angiogenic factor vascular endothelial growth factor (VEGF) can have direct effects in neurons and modulate processes such as neuronal migration, axon outgrowth, axon guidance and neuronal survival. Depending on the neuronal cell type and the process, VEGF seems to exert these effects by signaling via different receptors. It is also becoming clear that other VEGF ligands such as VEGF-B, -C and -D can act in various neuronal cell types as well. Moreover, apart from playing a role in physiological conditions, VEGF and VEGF-B have been related to different neurological disorders. We give an update on how VEGF controls different processes during neurodevelopment as well as on its role in several neurodegenerative disorders. We also discuss recent findings demonstrating that other VEGF ligands influence processes such as neurogenesis and dendrite arborization and participate in neurodegeneration.

Fig. 1

VEGF regulates neuronal migration. a VEGF controls migration of FBM neurons in the hindbrain. VEGF¹⁶⁴ binds to NRP1 expressed in the FBM soma and controls their migration in the soma from rhombomere 4 (r4) to rhombomere 6 (r6). Axon guidance of these neurons is not controlled by VEGF¹⁶⁴ but instead by semaphorin3A and semaphorin3F (SemaA/3F) which signal to receptor complexes formed by NRP1/PlxnA4 or NRP2/PlxnA3, respectively (adapted from Schwarz et al. [27]). b VEGF controls cerebellar granule cell migration during development. VEGF is expressed in Purkinje cells and controls granule cell migration from the external granule cell layer (EGL) towards the internal granule cell layer (IGL). Granule cells express VEGFR-2. VEGFR-2 forms a complex with NMDARs (NR1/NR2B) and VEGF signaling via VEGFR-2 induces the formation of VEGFR-2/NR1/NR2B receptor complexes and potentiates NMDAR-mediated currents and Ca²⁺ influx to control granule cell migration

Fig. 2

VEGF regulates axon growth and guidance. a VEGFR-2 regulates axon outgrowth of subicular neurons. Subicular neurons extend their axons (red) from the subiculum through the postcommissural fornix tract (pf). Sema3E is expressed in the CA1 and CA3 fields of the hippocampus (blue). Subicular neurons express VEGR-2. In these neurons, VEGFR-2 forms a multiprotein complex with NRP1 and PlexinD1 and becomes activated in a Sema3E-dependent/VEGF-independent manner. Activation of VEGFR-2 leads to activation of PI3K/Akt and axon growth. b VEGF regulates commissural axon guidance at the spinal cord midline. During spinal cord development VEGF is expressed in the floor plate (green). Commissural neurons and their axons projecting towards the ventral midline express VEGFR-2 (red). Floor plate-derived VEGF signals to VEGFR-2 in commissural axons, activates SFKs at the growth cone and induces growth cone turning, thus controlling axon guidance. c VEGF controls retinal ganglion cell (RGC) axon growth and guidance at the optic chiasm. VEGF is expressed at the optic chiasm (green). Certain RGC axons express NRP1 (red). VEGF binds to NRP1 and guides the axons across the midline to project in the contralateral side. NRP1⁻ RGC axons do not sense VEGF and are not attracted to the midline, and instead project ipsilaterally (blue)

Fig. 3

VEGF in neurodegenerative diseases. a Under normal conditions, HIF-1 is complexed with CBP/p300, binds to the HRE in the VEGF promoter and drives VEGF expression. b In VEGF^∂/∂ mice, the HRE is mutated and as a consequence there is a reduced expression of VEGF leading to motor neuron cell death and ALS. c In mutant SOD1G93A mice, SOD1^G93A destabilizes VEGF mRNA leading to less VEGF protein expression. d −22578C/A single nucleotide polymorphism. −2578A haplotype leads to reduced expression levels of VEGF and increases the risk of sporadic ALS in humans. e VEGF coaggregates with Aβ and is slowly released from the aggregates leading to reduced levels of available VEGF and neuronal and vascular dysfunction. f PolyQ-ATXN1 represses VEGF transcription leading to reduced levels of VEGF in the cerebellum and development of spinocerebellar ataxia type 1 (SCA1)

Fig. 4

VEGF in the nervous system. a VEGF exerts its effects in many different cell types in the nervous system. b VEGF has a pleiotropic role in the nervous systems and plays a role in the indicated processes (NEJ neuroeffector junction, NMJ neuromuscular junction)