Arteriogenesis
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Arteriogenesis refers to an increase in the
diameter In geometry, a diameter of a circle is any straight line segment that passes through the centre of the circle and whose endpoints lie on the circle. It can also be defined as the longest Chord (geometry), chord of the circle. Both definitions a ...
of existing arterial vessels.


Mechanical Stimulation

Mechanically, arteriogenesis is linked to elevated pressure, which increases radial wall stress, and elevated flow, which increases endothelial surface stress. The vessel increases in diameter until the stress is normalized (Prior ''et al.'', 2004). Arteriogenesis does not occur every time there is an increase in flow, however. Most vessel networks can handle increased flow without significantly increasing diameter because flow increases with the square (power 2) of the vessel diameter. Initial experiments demonstrated this phenomenon in that mature vessels are unlikely to respond to increased flow by increasing diameter, but will respond to decreased flow by decreasing diameter (Brownlee & Langille, 1991). Another experiment showed that increasing
shear stress Shear stress (often denoted by , Greek alphabet, Greek: tau) is the component of stress (physics), stress coplanar with a material cross section. It arises from the shear force, the component of force vector parallel to the material cross secti ...
caused an immediate increase in vessel expansion followed by a rapid decrease, as well as demonstrating that the mature vessels do indeed respond more favorably to decreased stress (Tuttle ''et al.'', 2001).


Chemical Stimulation


General

Chemically, arteriogenesis is related to upregulation of
cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
s and cell adhesion receptors. More specifically, mechanical stresses cause endothelial cells to produce chemical facilitators that begin the process of increasing diameter. An increase in shear stress causes an increase in the number of monocyte chemoattractant protein-1 (MCP-1) molecules expressed on the surface of vessel walls as well as increased levels of
TNF-α Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
,
bFGF Fibroblast growth factor 2 (FGF-2), also known as basic fibroblast growth factor (bFGF) and FGF-β, is a growth factor and signaling protein encoded by the ''FGF2'' gene. It binds to and exerts effects via specific fibroblast growth factor rece ...
, and MMP. MCP-1 increases the tendency of monocytes to attach to the cell wall. TNF-α provides an inflammatory environment for the cells to develop while bFGF helps induce mitosis in the endothelial cells. Finally, MMPs remodel the space around the artery to provide the space for expansion (Van Royen ''et al.'', 2001). Another potent chemical signal is
nitric oxide Nitric oxide (nitrogen oxide, nitrogen monooxide, or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes den ...
(NO), demonstrated to be a major factor in increasing vessel diameter in response to increased flow until the shear stress is restored to the normal level (Tronc ''et al.'', 1996).


bFGF

bFGF Fibroblast growth factor 2 (FGF-2), also known as basic fibroblast growth factor (bFGF) and FGF-β, is a growth factor and signaling protein encoded by the ''FGF2'' gene. It binds to and exerts effects via specific fibroblast growth factor rece ...
is known to increase both arteriogenesis and angiogenesis ''in vivo''. However, it is not sufficient as a monotherapy to increase arteriogenesis. In a placebo study determining the effects of bFGF on arteriogenesis, patients were treated with one bolus of bFGF. The treatment helped reduce anginal symptoms but did not significantly affect arteriogenesis. Thus, it is speculated that other growth factors work in tandem with bFGF to produce the desired response and that growth factors must be administered at varying time points throughout the duration of the experiment (Van Royen ''et al.'', 2001). This finding is important because it shows that arteriogenesis is the result of a combination of signaling cascades and growth factors as opposed to being tied to a single chemical.


CCL2

MCP1 (now called CCL2) is especially important in arteriogenesis. Since MCP-1 attracts monocytes it can produce an immune cascade to aid inflammation. Monocytes can enter the vessel wall to become macrophages and produce inflammatory cytokines such as
TNF-α Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
in addition to aiding the production of
bFGF Fibroblast growth factor 2 (FGF-2), also known as basic fibroblast growth factor (bFGF) and FGF-β, is a growth factor and signaling protein encoded by the ''FGF2'' gene. It binds to and exerts effects via specific fibroblast growth factor rece ...
and MMP (Van Royen ''et al.'', 2000). Macrophages also produce vascular endothelial growth factor (
VEGF Vascular endothelial growth factor (VEGF, ), 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 ...
) that is a huge contributor to the growth signaling of endothelial cells. Endothelial cells have a receptor devoted to VEGF aptly named VEGF receptor-1 that immediately signals rapid mitosis in the cells (Prior ''et al.'', 2004). One study showed that local infusion of MCP-1 caused a large increase in conductance in both collateral and peripheral vessels while diminished levels of MCP-1 hindered the process of arteriogenesis (Ito ''et al.'', 1997). This indicates that monocytes play a significant role in inducing arteriogenesis.


Applications of Arteriogenesis


Exercise

Poiseuille’s Law for flow indicates that the total flow in a tube is related to the diameter of the tube by a power of four. Thus, an increase in the diameter of a high order
blood vessel Blood vessels are the tubular structures of a circulatory system that transport blood throughout many Animal, animals’ bodies. Blood vessels transport blood cells, nutrients, and oxygen to most of the Tissue (biology), tissues of a Body (bi ...
such as an
arteriole An arteriole is a small-diameter blood vessel in the microcirculation that extends and branches out from an artery and leads to capillary, capillaries. Arterioles have vascular smooth muscle, muscular walls (usually only one to two layers of smoo ...
vastly increases the total flow that a given vessel network can withstand. This flow increase is vitally important in the microvasculature remodeling following exercise, especially in sprint training. Sprint training is a type of
anaerobic exercise Anaerobic exercise is a type of exercise that breaks down glucose in the body without using oxygen; ''anaerobic'' means "without oxygen". This type of exercise leads to a buildup of lactic acid. In practical terms, this means that anaerobic exe ...
that relies on having the maximum amount of blood available to the vessel network at any given time (Prior ''et al.'', 2004).


Atherosclerosis

Arteriogenesis also has much in common with the mechanisms of
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
. Monocytes invade the endothelial tissue, inflammatory
cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
s are released,
endothelial cell The endothelium (: endothelia) 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 th ...
s proliferate into the surrounding tissue, and cell adhesion receptors are upregulated. Presently, the effects of arteriogenesis on atherosclerosis are unknown, although MCP-1 receptors are known to be associated with plaque formation (Van Royen ''et al.'', 2001).


See also

*
angiogenesis 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 ...
*
anaerobic exercise Anaerobic exercise is a type of exercise that breaks down glucose in the body without using oxygen; ''anaerobic'' means "without oxygen". This type of exercise leads to a buildup of lactic acid. In practical terms, this means that anaerobic exe ...


References

{{Reflist, 30em


Sources

# Brownlee, R. D., & Langille, B. L. Arterial adaptions to altered blood flow. '' Can J Physiol Pharmacol'' 69: 978-83, 1991. # Ito WD, Arrasi M, Winkler B, Scholz D, Schaper J, and Schaper W. Monocytochemotactic protein-1 increases collateral and peripheral conductance after femoral artery occlusion. ''Circ Res'' 80: 829–837, 1997. # Prior, B. M., Yang, H. T., & Terjung, R. L. What makes vessels grow with exercise training? ''J App Physiol'' 97: 1119-28, 2004. # Tronc F, Wassef M, Exposito B, Henrion D, Glagov S, and Tedgui A. Role of NO in flow-induced remodeling of the rabbit common carotid artery. ''Arterioscler Thromb Vasc Biol'' 16: 1256–1262, 1996. # Tuttle, J. L., Nachreiner, R. D., Bhuller, A. S., Condict, K. W., Connors, B. A., & Herring, B. P. ''et al.'' Shear level influences resistance artery remodeling: Wall dimensions, cell density, and eNOS expression. ''Am J Physiol Heart Circ Physiol'' 281: H1380-H1389, 2001. # Van Royen N, Piek JJ, Buschmann I, Hoefer I, Voskuil M, and Schaper W. Stimulation of arteriogenesis: a new concept for the treatment of arterial occlusive disease. ''Cardiovasc Res'' 49: 543–553, 2001. Angiology