Neuroangiogenesis

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Neuroangiogenesis is the coordinated growth of nerves and blood vessels. [1] 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 [2] 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. [3] It is thought to have a role in pathologies such as endometriosis, [4] brain tumors, [5] and Alzheimer's disease. [6]

Contents

Physiology

Neurovascular patterning

Neurovascular development is the parallel emergence and patterning of the nervous system and the vascular system during embryogenesis and early life. [3] [5] Neurovascular congruency appears to be determined by shared molecular patterning mechanism involving axon guidance that involves axonal guidance molecules such as sema3A (semaphorin 3A) and (neuropilin). [7]

Mechanisms

Neuroangiogenic and axonal guidance molecules act on both neuronal growth cones and endothelial tip cells in order to guide growth. [5]

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 (red in image) and microtubule (green in image) cytoskeleton. [8]

Neuronal growth cone Growthcone.jpg
Neuronal growth cone

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. [8]

Neurogenic factors

There are many neuroangiogenic factors, some of which act to promote neuronal growth and vice versa. [5] The table shows examples

Neuroangiogenic factorEffect on neuronEffect on vascular endothelial cellsReceptor/LigandOrigin
IGF-1 Promotion of neurogenesis and synaptogenesis EC proliferation, migration, and differentiation Ligand Liver cells
bFGF Proliferation of cortical progenitors and neurogenesisEC proliferation, migration, and differentiation Ligand Adipocytes
NGF Neuron survival, differentiationPromotion of angiogenesis and arteriogenesis in ischemic hindlimbsLigandMultiple
Neuropilin Axon guidance Synergistic action of VEGF165 in EC migration and proliferation
Vascular development
ReceptorTarget cell
VEGF Neuronal development and patterning, and has neurotrophic and neuroprotective effectsInduces angiogenesis, promotes endothelial cell survival, proliferation and migrationLigandMultiple

Pathology

Neuroangiogenesis is implicated in a number of pathologies, including endometriosis, [4] brain tumors, [5] and senile dementias, such as Alzheimer's disease. [6] 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. [5] [9]

Endometriosis

Endometriosis is a common gynaecological disease caused by endometrial tissue implanting outside the uterus, 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.[ citation needed ] One possible explanation for this is the simultaneous growth of neurons into these areas alongside blood vessels through neuroangiogenesis. [4]

Brain tumors

Brain tumors, such as glioblastoma multiforme, are characterized by dense vascularity associated with high expression of the proangiogenic factors, VEGF and interleukin 8. [5]

Brain injury

Following ischemic stroke or traumatic brain injury, angiogenesis supports oxygen and nutrient re-supply to injured tissue, and stimulates neurogenesis and synaptogenesis, particularly in the ischemic penumbra. [5] Neuroangiogenesis is finely regulated and sequential, involving proliferation and migration of endothelial cells to restore blood–brain barrier function, recruitment of pericytes, and stabilization new blood vessels, a process dependent on upregulation of proangiogenic factors, such as VEGF and angiopoietin-1. [5]

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 and hence, by inference, cerebral blood flow and cognitive ability decline. [5] [6] 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. [5] [6] [10]

See also

Related Research Articles

<span class="mw-page-title-main">Capillary</span> Smallest type of blood vessel

A capillary is a small blood vessel, from 5 to 10 micrometres in diameter, and is part of the microcirculation system. Capillaries are microvessels and the smallest blood vessels in the body. They are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the site of the exchange of many substances from the surrounding interstitial fluid, and they convey blood from the smallest branches of the arteries (arterioles) to those of the veins (venules). Other substances which cross capillaries include water, oxygen, carbon dioxide, urea, glucose, uric acid, lactic acid and creatinine. Lymph capillaries connect with larger lymph vessels to drain lymphatic fluid collected in microcirculation.

<span class="mw-page-title-main">Angiogenesis</span> Blood vessel formation, when new vessels emerge from existing vessels

Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and splitting, but processes such as coalescent angiogenesis, vessel elongation and vessel cooption also play a role. Vasculogenesis is the embryonic formation of endothelial cells from mesoderm cell precursors, and from neovascularization, although discussions are not always precise. The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease.

<span class="mw-page-title-main">Haemodynamic response</span>

In haemodynamics, the body must respond to physical activities, external temperature, and other factors by homeostatically adjusting its blood flow to deliver nutrients such as oxygen and glucose to stressed tissues and allow them to function. Haemodynamic response (HR) allows the rapid delivery of blood to active neuronal tissues. The brain consumes large amounts of energy but does not have a reservoir of stored energy substrates. Since higher processes in the brain occur almost constantly, cerebral blood flow is essential for the maintenance of neurons, astrocytes, and other cells of the brain. This coupling between neuronal activity and blood flow is also referred to as neurovascular coupling.

<span class="mw-page-title-main">Pericyte</span> Cells associated with capillary linings

Pericytes 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 capillaries, where they communicate with endothelial cells by means of both direct physical contact and paracrine signaling. The morphology, distribution, density and molecular fingerprints of pericytes vary between organs and vascular beds. Pericytes help to maintain homeostatic and hemostatic functions in the brain, one of the organs with higher pericyte coverage, and also sustain the blood–brain barrier. These cells are also a key component of the neurovascular unit, which includes endothelial cells, astrocytes, and neurons. Pericytes have been postulated to regulate capillary blood flow and the clearance and phagocytosis of cellular debris in vitro. Pericytes stabilize and monitor the maturation of endothelial cells by means of direct communication between the cell membrane as well as through paracrine signaling. A deficiency of pericytes in the central nervous system can cause increased permeability of the blood–brain barrier.

Vascular endothelial growth factor, originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis and angiogenesis.

Vasculogenesis is the process of blood vessel formation, occurring by a de novo production of endothelial cells. It is sometimes paired with angiogenesis, as the first stage of the formation of the vascular network, closely followed by angiogenesis.

<span class="mw-page-title-main">Neuropilin</span> Protein receptor active in neurons

Neuropilin is a protein receptor active in neurons.

<span class="mw-page-title-main">VEGF receptor</span> Protein family

VEGF receptors (VEGFRs) are receptors for vascular endothelial growth factor (VEGF). There are three main subtypes of VEGFR, numbered 1, 2 and 3. Depending on alternative splicing, they may be membrane-bound (mbVEGFR) or soluble (sVEGFR).

<span class="mw-page-title-main">Subgranular zone</span>

The subgranular zone (SGZ) is a brain region in the hippocampus where adult neurogenesis occurs. The other major site of adult neurogenesis is the subventricular zone (SVZ) in the brain.

<span class="mw-page-title-main">Neuropilin 2</span> Protein-coding gene in the species Homo sapiens

Neuropilin 2 (NRP2) is a protein that in humans is encoded by the NRP2 gene.

<span class="mw-page-title-main">Neuropilin 1</span> Protein-coding gene in the species Homo sapiens

Neuropilin-1 is a protein that in humans is encoded by the NRP1 gene. In humans, the neuropilin 1 gene is located at 10p11.22. This is one of two human neuropilins.

<span class="mw-page-title-main">Placental growth factor</span> Protein-coding gene in the species Homo sapiens

Placental growth factor(PlGF) is a protein that in humans is encoded by the PGF gene.

<span class="mw-page-title-main">Semaphorin-3A</span> Protein-coding gene in the species Homo sapiens

Semaphorin-3A is a protein that in humans is encoded by the SEMA3A gene.

<span class="mw-page-title-main">Vascular endothelial growth factor B</span> Protein-coding gene in the species Homo sapiens

Vascular endothelial growth factor B also known as VEGF-B is a protein that, in humans, is encoded by the VEGF-B gene. VEGF-B is a growth factor that belongs to the vascular endothelial growth factor family, of which VEGF-A is the best-known member.

<span class="mw-page-title-main">Vascular endothelial growth factor A</span> Protein involved in blood vessel growth

Vascular endothelial growth factor A (VEGF-A) is a protein that in humans is encoded by the VEGFA gene.

Angiogenesis is the process of forming new blood vessels from existing blood vessels, formed in vasculogenesis. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during normal physiological development, but it also occurs in adults during inflammation, wound healing, ischemia, and in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth. Proteolysis has been indicated as one of the first and most sustained activities involved in the formation of new blood vessels. Numerous proteases including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase domain (ADAM), a disintegrin and metalloproteinase domain with throbospondin motifs (ADAMTS), and cysteine and serine proteases are involved in angiogenesis. This article focuses on the important and diverse roles that these proteases play in the regulation of angiogenesis.

<span class="mw-page-title-main">Vascular remodelling in the embryo</span> Biological process

Vascular remodelling is a process which occurs when an immature heart begins contracting, pushing fluid through the early vasculature. The process typically begins at day 22, and continues to the tenth week of human embryogenesis. This first passage of fluid initiates a signal cascade and cell movement based on physical cues including shear stress and circumferential stress, which is necessary for the remodelling of the vascular network, arterial-venous identity, angiogenesis, and the regulation of genes through mechanotransduction. This embryonic process is necessary for the future stability of the mature vascular network.

<span class="mw-page-title-main">Pathophysiology of Parkinson's disease</span> Medical condition

The pathophysiology of Parkinson's disease is death of dopaminergic neurons as a result of changes in biological activity in the brain with respect to Parkinson's disease (PD). There are several proposed mechanisms for neuronal death in PD; however, not all of them are well understood. Five proposed major mechanisms for neuronal death in Parkinson's Disease include protein aggregation in Lewy bodies, disruption of autophagy, changes in cell metabolism or mitochondrial function, neuroinflammation, and blood–brain barrier (BBB) breakdown resulting in vascular leakiness.

Vasohibin-2 (VASH2) is a multifaceted protein that is encoded for by the VASH2 gene. As a vasohibin protein, VASH2 is closely associated with the vascular endothelial growth factor (VEGF) family of proteins as well. VASH2 has therefore been implicated in playing a vital role in blood vessel generation (angiogenesis), especially as it relates to tumor growth, but it has also been observed in association with neuron differentiation as well as ameliorating the symptoms of diabetic nephropathology.

<span class="mw-page-title-main">Neurovascular unit</span>

The neurovascular unit (NVU) comprises the components of the brain that collectively regulate cerebral blood flow in order to deliver the requisite nutrients to activated neurons. The NVU addresses the brain's unique dilemma of having high energy demands yet low energy storage capacity. In order to function properly, the brain must receive substrates for energy metabolism–mainly glucose–in specific areas, quantities, and times. Neurons do not have the same ability as, for example, muscle cells, which can use up their energy reserves and refill them later; therefore, cerebral metabolism must be driven in the moment. The neurovascular unit facilitates this ad hoc delivery and, thus, ensures that neuronal activity can continue seamlessly.

References

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