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 increasing diameter because flow is related to vessel diameter by a power of four. 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 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).

General

Chemically, arteriogenesis is related to upregulation of cytokine

Cytokine

Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

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, bFGF, and MMP

MMP

MMP is a three letter acronym that may refer to:*International Organization of Masters, Mates & Pilots , a maritime labor union*Manitoba Marijuana Party, now Freedom Party of Manitoba, a Canadian political party* Mathematics-Mechanization Platform...

. 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 (NO

NO

NO, N.O., No, or No. may refer to:* One of a pair of English words, yes and no, which signal confirmation or a negative response respectively.- Geographical locations :* Norway, ISO 3166-1 country code* Lake No, Sudan...

), 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 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.

MCP-1

MCP-1 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 in addition to aiding the production of bFGF and MMP

MMP

MMP is a three letter acronym that may refer to:*International Organization of Masters, Mates & Pilots , a maritime labor union*Manitoba Marijuana Party, now Freedom Party of Manitoba, a Canadian political party* Mathematics-Mechanization Platform...

 (Van Royen et al., 2000). Macrophages also produce vascular endothelial growth factor (VEGF

Vascular endothelial growth factor

Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....

) 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.

Exercise

Poseuille’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 vessel

The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...

 such as an arteriole

Arteriole

An arteriole is a small diameter blood vessel in the microcirculation that extends and branches out from an artery and leads to capillaries.Arterioles have muscular walls and are the primary site of vascular resistance...

 vastly increases the total flow that a given vessel network can withstand. This flow increase is vitally important in the microvasculature remodeling

Microvasculature remodeling

Microvasculature remodeling refers to the alterations in a blood vessel network resulting from arteriogenesis and angiogenesis. Briefly, arteriogenesis is an increase in arterial diameter while angiogenesis is an increase in the number of capillaries either by sprouting from or splitting existing...

 following exercise, especially in sprint training. Sprint training is a type of anaerobic exercise

Anaerobic exercise

Anaerobic exercise is exercise intense enough to trigger anaerobic metabolism. It is used by athletes in non-endurance sports to promote strength, speed and power and by body builders to build muscle mass...

 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

Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...

. Monocytes invade the endothelial tissue, inflammatory cytokine

Cytokine

Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

s are released, endothelial cells 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).