© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Arteriogenesis, the good and bad of it
Department for Experimental Cardiology, Max-Planck-Institute for Physiological and Clinical Research, Bad Nauheim, Germany
* Corresponding author. Tel.: +49-6032-705-402; fax: +49-6032-705-419 w.schaper{at}kerckhoff.mpg.de
Received 31 May 1999; accepted 31 May 1999
Arteriolar vessels that interconnect adjacent vascular territories in the form of networks or arcades exist normally in the skeletal [1] and cardiac muscle [2] of most mammals including man. They function usually as a means of efficient flow distribution, to act as capacitors for blood displacement in non-synchronously contracting muscles or are just remnants of the embryonic vascular network that has not fully reached its full determination.
These vessels can expand by growth when pressure gradients develop, the most likely cause of which is the unilateral fall in pressure by a stenosis or occlusion of one of the arteries that feed into the network [2]. Although total blood flow into the network is now reduced (or unaltered due to compensating vasodilation) the velocity of blood flow in the vessels representing the shortest connection to the distal distribution of the occluded vessel is markedly increased. This creates an increase in the fluid shear stress [3] in the shortest pathway within the network which activates the endothelium.
Activated endothelium has a typical synthetic and proliferative phenotype (increased endoplasmic reticulum, free ribosomes, loss of volume control, swelling) and is characterized by upregulation of adhesion molecules [2] and of monocyte chemoattractant protein (MCP-1) [4]. As a result of activation, monocytes adhere to the endothelium, become activated themselves and produce TNF-alpha and several other growth factors, cytokines and chemokines [5,6]. This starts the vascular growth which begins with endothelial proliferation which is soon followed by that of smooth muscle. Parallel with proliferation, or maybe preceding it, proteolytic activity starts to create the space for the expanding vessel and to remodel the given structures of the vessel itself [7]. This begins with the digestion of the internal elastic lamina, and the lysis of the extracellular matrix which enables the smooth muscle layers to slide under the influence of the intravascular pressure, thereby enlarging the vessel passively at first, giving it a vein-like appearance. This is followed by new smooth muscle which arranges itself in two directions: circular and longitudinal, the latter forming the neointima [8]. In a typical dog heart, where one or two of the epicardial arteries had been slowly occluded, the collateral vessels increase their diameter by a factor of 20 times their internal diameter and the tissue mass increases by 50-fold. This is only possible by mitosis of the vascular cells. The mitotic index of the endothelial and smooth muscle cell populations increase up to over 100-fold at the maximum of growth activity [2].
Most of the growth factors that are needed for mitosis are already present in the tissue (the FGF’s are stored in the extracellular matrix) or they are produced by invading cells like the monocytes, but also T-cells and basophiles transforming into mastcells are producers of growth factors. Several of the growth factors are produced constitutively at low levels (VEGF, FGF-1 and-2) and their rate of transcription can be increased within a very short time or the stability of their respective mRNA’s can be drastically increased within minutes [9,10]
The abundance of the growth factors under physiological conditions and the inefficiency of growth factor application under non-pathological conditions suggest that the growth factor receptors are downregulated normally. An acute occlusion of the femoral artery in the rabbit upregulates the FGF-receptors for a limited time window of 12 h (mRNA) and makes the tissue receptive for growth factor action. This means that the regulation of arteriogenesis is achieved via the availability of the receptors and not the ligands [9].
The invading monocytes become activated themselves in the process of adherence to the activated endothelium: under the stimulation by MCP-1, secreted by the activated endothelium or infused intraarterially for experimental arteriogenic therapy, they express tissue factor, MIP-1 alpha and MIP-1 beta, as well as IL-8. These cyto- and chemokines exert a procoagulative effect [11,12].
In addition to the pro-inflammatory effects of arteriogenesis (invasion of mononuclear cells, perivascular inflammation during the early stages) [13,14] the procoagulative effect adds to the pro-atherogenic effect and it will become a very important issue in the development of an arteriogenic medicine to balance the ‘good’ against the ‘bad’ effects.
MCP-1, the most potent of the arteriogenic stimulants, is also one of the most potent atherogenic peptides because of its chemotactic effects on monocytes that invade plaques and convert into foam cells. But this contrasting spectrum of effects is not exclusive to MCP-1, it is also shared by VEGF that is overexpressed in human arterial biopsy material, leads to the formation of vasa vasorum which may rupture and bleed or vascularization of plaques that may rupture themselves under the pressure of ruptured and bleeding new vessels. In addition, VEGF induces, like MCP-1, the expression of tissue factor in monocytes and is thus prothrombotic.
Although the ‘good’ effects of arteriogenesis dominate under experimental conditions in otherwise healthy animals undergoing acute or chronic occlusions, the end result, even under ideal experimental conditions, is far from a constitutio ad integrum: only about one third of the maximal conductance of the artery before occlusion is obtained by the arteriogenic process. It is unknown why the process stops prematurely, but probably because the shear stress that had been driving it had fallen under a critical value due to the enlargement of the collateral vessels.
A characteristic feature of collateral vessels is their tortuosity: they grow in length as well in width [2]. To accommodate the unneeded extra length the vessel arranges in loops and turns. This may reflect the genetically determined embryonic development where vessels always grow in length and in width. Arteriogenesis in the adult organ is most probably a recapitulation of embryonic angiogenesis and arteriogenesis.
The tortuosity of collateral vessels is the cause of energy losses and one of the causes of non-ideal adaptation: the extra length as well as the curvature and the non-physiological angle of entering the recipient distribution system cause frictional energy losses that are reflected in marked reductions of distal pressure with only moderately increasing flows. Part of these pressure losses can be prevented by additionally induced growth via external application of growth factors, but it will perhaps not be entirely avoidable. To prevent longitudinal growth will be the answer, but at present it remains unknown how to achieve this.
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Conventional wisdom states that vascular growth in the adult organism is usually associated with tissue hypoxia/ischemia, with the exception of angiogenesis in the female reproductive tract, arteriogenesis of the uterine artery during pregnancy. There is no doubt that angiogenesis, the sprouting of new capillaries from preexisting ones [14], is mainly caused by hypoxia: VEGF [15] is upregulated by activation of a variant of the ‘hypoxia-inducible factor’ hif-1, a nuclear protein which binds to responsive sequence in the VEGF promotor, thereby increasing transcription. Furthermore, a RNA binding protein is activated in the cytoplasm that binds to various regions of the VEGF mRNA and prevents its degradation. While this mechanism remains undisputed for angiogenesis, it is most probably not applicable for arteriogenesis because arteriogenesis proceeds in an environment that is not ischemic, or much less ischemic than tissue where angiogenesis occurs. In an animal model of femoral artery occlusion only the lower leg becomes transiently ischemic and angiogenic, but not the upper leg where arteriogenesis occurs [13]. This is also reflected in the human situation where gangrene of the big toe develops but bridging collaterals occur in the upper thigh. The occurrence of small foci of ischemia cannot be excluded in the vicinity of growing arteries, especially not since these develop preferentially within aerobic red skeletal muscles. However, ischemia is an unlikely stimulus for arteriogenesis because VEGF, the only growth factor with a clear connection to hypoxia, is not a mitogen for smooth muscle cells and is not induced near or in growing collaterals.
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Arteriogenesis, the process of collateral artery growth as an adaptation to major arterial occlusion, can be life- and tissue saving and may alter the natural course of the consequences and organ manifestations of arterial disease. This is achieved by an active growth process that is coupled to complete arterial remodeling with activation of proteases and destruction of the organ tissue in the immediate vicinity of the growing vessel, to create the space for a new artery which expands to about 20 times its original diameter. Much of the growth and remodeling is achieved by attraction, adhesion, activation and invasion of circulating cells, mostly monocytes, but also T-cells and basophiles. Growth factors that are already present, as well as those that are produced by invading cells, produce an environment of inflammation and facilitate coagulation and are therefore pro-atherogenic. It will be a challenge for future therapies with growth factors, chemokines and cytokines to neutralize the atherogenic and to maximize their arteriogenic properties.
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This review is a summary of the Basic Science Lecture delivered by Wolfgang Schaper at the Annual Congress of The European Society of Cardiology, Vienna, August 1998. This manuscript will be simultaneously published by The European Heart Journal and Cardiovascular Research. 
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[Abstract/Free Full Text]
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