Neuroangiogenesis is the coordinated growth of nerves and blood vessels. The nervous and blood vessel systems share guidance cues and cell-surface receptors allowing for this synchronised growth. The term ''neuroangiogenesis'' only came into use in 2002 and the process was previously known as neurovascular patterning. The combination of neurogenesis and angiogenesis is an essential part of embryonic development and early life. It is thought to have a role in pathologies such as endometriosis,

brain tumor A brain tumor occurs when abnormal cells form within the brain. There are two main types of tumors: malignant tumors and benign (non-cancerous) tumors. These can be further classified as primary tumors, which start within the brain, and seconda ...

s, and Alzheimer's disease.

Physiology

Neurovascular patterning

Neurovascular development is the parallel emergence and patterning of the nervous system and the vascular system during embryogenesis and early life. Neurovascular congruency appears to be determined by shared molecular patterning mechanism involving axon guidance that involves axonal guidance molecules such as

sema3A Semaphorin-3A is a protein that in humans is encoded by the ''SEMA3A'' gene. Function The ''SEMA3A'' gene is a member of the semaphorin family and encodes a protein with an Ig-like C2-type (immunoglobulin-like) domain, a PSI domain and a Sem ...

(

semaphorin Semaphorins are a class of secreted and membrane proteins that were originally identified as axonal growth cone guidance molecules. They primarily act as short-range inhibitory signals and signal through multimeric receptor complexes. Semaphorins ...

3A) and (

neuropilin Neuropilin is a protein receptor active in neurons. There are two forms of Neuropilins, NRP-1 and NRP-2. Neuropilins are transmembrane glycoproteins, first documented to regulate neurogenesis and angiogenesis by complexing with Plexin recepto ...

Mechanisms

Neuroangiogenic and axonal guidance molecules act on both neuronal growth cones and endothelial tip cells in order to guide growth. Neuronal growth cones are situated on the tips of nerve cells and are responsive to different factors, both positive and negative. Growth of the neuron occurs by an extension of the

actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...

(red in image) and microtubule (green in image) cytoskeleton. Growthcone

Tip cells found at the extremity of the developing blood vessel control adjacent endothelial cells to direct growth. Tip cells have receptors and ligands via which they respond to local neuroangiogenic factors.

Neurogenic factors

There are many neuroangiogenic factors, some of which act to promote neuronal growth and vice versa. The table shows examples

Pathology

Neuroangiogenesis is implicated in a number of pathologies, including endometriosis, brain tumors, and senile

dementias Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affec ...

, such as Alzheimer's disease. Each of these incurs a significant cost for the healthcare industry, meaning that complete understanding of processes involved – including neuroangiogenesis – is necessary to enable development of functional treatments.

Endometriosis

Endometriosis is a common gynaecological disease caused by endometrial tissue implanting outside the

uterus The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The ...

, a symptom of which is chronic pelvic pain. The formation, growth and persistence of these implants are dependent upon angiogenesis to increase the supply of blood vessels. The resulting increase in blood flow may correlate directly with pain symptoms. One possible explanation for this is the simultaneous growth of neurons into these areas alongside blood vessels through neuroangiogenesis.

Brain tumors

Brain tumors, such as

glioblastoma multiforme Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality cha ...

, are characterized by dense vascularity associated with high expression of the proangiogenic factors, VEGF and

interleukin 8 Interleukin 8 (IL-8 or chemokine (C-X-C motif) ligand 8, CXCL8) is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells. Endothelial cells store IL-8 in their storage ...

Brain injury

Following

ischemic stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop funct ...

traumatic brain injury A traumatic brain injury (TBI), also known as an intracranial injury, is an injury to the brain caused by an external force. TBI can be classified based on severity (ranging from mild traumatic brain injury TBI/concussionto severe traumatic br ...

, angiogenesis supports oxygen and nutrient re-supply to injured tissue, and stimulates neurogenesis and

synaptogenesis Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenes ...

, particularly in the ischemic penumbra. Neuroangiogenesis is finely regulated and sequential, involving proliferation and migration of

endothelial cells The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...

to restore blood–brain barrier function, recruitment of

pericytes Pericytes (previously known as Rouget cells) are multi-functional mural cells of the microcirculation that wrap around the endothelial cells that line the capillaries throughout the body. Pericytes are embedded in the basement membrane of blood c ...

, and stabilization new blood vessels, a process dependent on

upregulation In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary proc ...

of proangiogenic factors, such as VEGF and

angiopoietin-1 Angiopoietin is part of a family of vascular growth factors that play a role in embryonic and postnatal angiogenesis. Angiopoietin signaling most directly corresponds with angiogenesis, the process by which new arteries and veins form from pre ...

Alzheimer’s disease

A condition possibly resulting from a reduction in neuroangiogenic factors is Alzheimer’s disease. Without continued neuroangiogenesis during aging, areas of the brain may no longer have the full complement of functional

capillaries A capillary is a small blood vessel from 5 to 10 micrometres (μm) in diameter. Capillaries are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the smallest blood vessels in the body: ...

and hence, by inference,

cerebral blood flow Cerebral circulation is the movement of blood through a network of cerebral arteries and veins supplying the brain. The rate of cerebral blood flow in an adult human is typically 750 milliliters per minute, or about 15% of cardiac output. Art ...

and

cognitive ability Cognitive skills, also called cognitive functions, cognitive abilities or cognitive capacities, are brain-based skills which are needed in acquisition of knowledge, manipulation of information and reasoning. They have more to do with the mechanisms ...

decline. This condition of reduced neuroangiogenesis and lower capillary density during senescence, possibly involving impaired regulation of angiogenic factors by hypoxia, could be a vascular basis for Alzheimer's disease.

References

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