1. Blood Vessels and Nerves Common Signals, Pathways and Diseases

2. Neural and Vascular Cell Fate

3. Neural and vascular cell fate In the neural tube (NT), LATERAL INHIBITION through Notch signalling maintains neuroectodermal stem cell (NSC) potential, and low Notch allows neuronal cell differentiation. Gradients of sonic hedgehog (Shh), which is produced by the notochord (N), and bone morphogenetic protein (BMP) determine the ventral and dorsal identity of neural progenitorsand induce distinct neuronal cell subtypes in a dose-dependent fashion along the MORPHOGEN gradient, which explains why distinct types of neuron arise at different locations — for example, MOTOR NEURONS arise more ventrally than interneurons in the spinal cord. Notochord-derived Shh induces somites to release vascular endothelial growth factor (VEGF), which — through Notch signalling — induces arterial endothelial cell (EC) fate at the expense of venous EC fate.

4. Neural stem cells at the vascular niche

5. Neuroectodermal stem cells (NSCs) at the subventricular zone (SVZ) lie in the vicinity of the EPENDYMAL CELL layer, which produces vascular endothelial growth factor (VEGF), at a vascular niche of numerous capillaries. A shortage of oxygen during physical exercise or stroke upregulates VEGF levels, which stimulate both NSCs and capillaries to grow, and enhance neuronal differentiation, axon outgrowth and neuron survival. The favourable effect of endothelial cells on neurogenesis is, at least in part, mediated by the release of brain-derived neurotrophic factor (BDNF). BV, blood vessel.

6. Role of Ephrin/Eph interactions in neural crest migration and intersegmental-vessel branching

7. Role of ephrin/Eph interactions in neural crest migration and intersegmental-vessel branching Neural crest cells migrate only into and through the rostral half of the somite, and avoid the caudal half because of repulsive EphB/ephrin-B interactions. Intersegmental vessels (ISVs) branch at regularly spaced sites and are guided to migrate through the somites, but are repelled from entry into the somites through repulsive EphB/ephrin-B signals. Ao, aorta.

8. A balance of Sema3A and VEGF determines Nrp1 mediated growth-cone guidance

9. The filopodia of both endothelial cells (ECs) and axons express neuropilin-1 (Nrp1): the semaphorin Sema3A repels (jagged arrow) the filopodia, whereas vascular endothelial growth factor VEGF164 attracts the filopodia, which drives the EC or axon to move in the direction of the VEGF gradient. The role of VEGF is best characterized for ECs.

10. Role of matrix association of VEGF in vessel branching

11. Long-range vascular endothelial growth factor (VEGF) gradients allow endothelial cells (ECs) to maintain their directional course to the target cell, whereas short-range matrix-bound VEGF guideposts are necessary for ECs to migrate step-by-step along the journey. a | In the absence of heparin- binding VEGF164 and VEGF188, there is insufficient guidance by short- range matrix-associated VEGF. The soluble VEGF120 is freely diffusible, chaotically distributed and fails to provide a directional long-range guidance cue.As a result, ECs in a single vessel move in all directions, which leads to vessel expansion rather than directional branching. b | The VEGF164 isoform provides both short-range matrix guideposts and a long- range gradient of attractant, which allows the vessel to send long sprouts straight to the target. c | When only matrix bound VEGF188 is present, there is no long-range attraction, and EC filopodia are misguided over short distances, often taking wrong turns. ECM, extracellular matrix.

12. Coordinated patterning of nerves with blood vessels

13. a | Artemin (ARTN) is a vessel-derived neurotropic guidance signal for sympathetic nerve axons; its expression in the vascular smooth muscle cells (SMCs), from which it is secreted, gradually shifts distally and thereby guides the sympathetic nerve fibre to the target organ. b | Vascular endothelial growth factor (VEGF) is a nerve- derived arteriotropic guidance signal for small arteries; its expression in, and secretion from, Schwann cells attracts and induces arteries, but not veins, to track alongside the nerve fibres.

15. Role of VEGF in motor neuron degeneration

16. a | In the spinal cord, vascular endothelial growth factor (VEGF) levels must be regulated to maintain adequate perfusion; however, VEGF is also neurotrophic and stimulates the survival of motor neurons. b | Insufficient VEGF levels cause chronic ISCHAEMIA and deprive motor neurons of essential survival signals, which results in adult-onset motor neuron degeneration that is reminiscent of amyotrophic lateral sclerosis (ALS)