An intricate sensory network intertwined across our bodies, the nervous system requires a specialized network of blood vessels for its development and survival.  However, it is still unclear as to how these nerves attract blood vessels with several animal studies suggesting the formation of blood vessels requires cross-talk between developing tissue and specialized endothelial cells.  Now, a study from researchers at Karlsruhe Institute of Technology (KIT) shows blood vessel growth is modulated by neurons and not, as assumed, through the communication of the vessel cells between each other. The team states their results are groundbreaking for research into the treatment of cancer-based, vascular, and neurodegenerative diseases. The opensource study is published in the journal Nature Communications.

Previous studies have indicated blood vessels more or less regulate their own growth, with soluble FMS-like tyrosine kinase-1 (1sFlt1), and VEGF growth factor implicated in the process. Recent studies show in the case of oxygen deficiency, tissue releases VEGF to attract the blood vessels carrying VEGF receptors on their surfaces. The current study investigates how blood vessel growth is regulated at the time of birth.

The current study utilizes fluorescent dyes, biochemical, and genetic analysis to document the colonization of neuronal stem cells and subsequent vascular budding in the vertebral canal of zebrafish.  Results show at different development stages, the nerve cells of the spinal cord produce more or less sFlt1 and VEGF to modulate the development of blood vessels.  Data findings show spinal cord vascularization proceeds from veins involving two-tiered regulation of neuronal sFlt1 to put the brakes on growth and VEGF to promote proliferation via a novel sprouting mode.

Results show at the early developmental stage, neuronal sFlt1 dampens blood vessel growth by binding and inactivating the growth factor VEGF.  Data findings show in the spinal cord, this creates an environment poor in oxygen, essential to the early development of the neuronal stem cells. The lab observed as nerve cell differentiation increases the concentration of the soluble sFlt1 decreases continuously, and the brake on vascular growth is loosened because more active VEGF is now available.  They conclude subsequently, blood vessels grow into the young spinal cord to provide it with oxygen and nutrients.

The group states the concentration of the growth factor is crucial to the density of the developing blood vessel network.  They go on to add when sFlt1 was switched off completely in nerve cells a dense network of blood vessels formed which grew into the vertebral canal, with the growth of blood vessels suppressed when sFIt1 is increased. The researchers note even small variations in substance concentration led to severe vascular developmental disorders.

The team surmises their study shows neurons regulate blood vessel network density and architecture in the development stage via the modulation of sFlt1 and VEGF.  For the future, the researchers state their work provides a completely new perspective on how blood vessels grow, branch out, or are inhibited in their growth. 

Source: Karlsruhe Institute of Technology (KIT)

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