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Acta Biochim Biophys
Sin 2008, 40: 681-692
doi:10.1111/j.1745-7270.2008.00436.x
Mechanisms of arteriogenesis
Weijun Cai1* and Wolfgang
Schaper2*
1
Department of
Anatomy and Neurobiology, Xiangya School of Medicine, Central South University,
Changsha, China
2
Max-Planck-Institute
for Heart and Lung Research, Arteriogenesis Research Group, Bad Nauheim,
D-61231, Germany
Received: April 17,
2008
Accepted: May 28,
2008
This work was supported by a grant from the National Science
Foundation of China (No. 30771134) and the Kuehl Foundation of Germany*Corresponding
authors:
Wolfgang Schaper:
Tel, 49-6032-705409; Fax, 49-6032-705458; E-mail, [email protected]
Weijun
Cai: Tel, 86-731-2650422; Fax, 86-731-2650426; E-mail, [email protected]
Patients with
occlusive atherosclerotic vascular diseases have frequently developed collateral
blood vessels that bypass areas of arterial obstructions. The growth of these
collateral arteries has been termed “arteriogenesis”, which describes
the process of a small arteriole’s transformation into a much larger
conductance artery. In recent years, intensive investigations using various
animal models have been performed to unravel the molecular mechanisms of
arteriogenesis. The increasing evidence suggests that arteriogenesis seems to
be triggered mainly by fluid shear stress, which is induced by the altered
blood flow conditions after an arterial occlusion. Arteriogenesis involves
endothelial cell activation, basal membrane degradation, leukocyte invasion,
proliferation of vascular cells, neointima formation (in most species studied),
changes of the extracellular matrix and cytokine participation. This paper is
an in-depth review of the research critical to recent advances in the field of
arteriogenesis that have provided a better understanding of its mechanisms.
Keywords arteriogenesis; shear stress; ischemic; remodeling; artery
The study of arteriogenesis, the development of an arterial
circulation circumventing the occlusion of a large artery from pre-existent or de
novo small arterioles, has overcome three much-debated hurdles during the
last 100 years. First, the existence of precursor structures was anatomically
proven; second, the precursor structures’ function under normal and
pathological conditions was demonstrated; and third, it was shown that
biological or pharmacological agents can influence collateral artery
development. However, there is one hurdle that this field has yet to overcome:
the treatment of human patients with new arteriogenic agents.Commenting on the importance of arteriogenesis, William F.M. Fulton,
a pioneer in the field of the human coronary collateral circulation, once said,
“If some means could emerge of encouraging the rate at which normal
coronary arterial anastomoses enlarge to form the wide channels for collateral
blood flow, then a considerable potential advantage would be gained in the
management of ischemic heart disease [1].” Similar words could easily have
been applied to peripheral, cerebral and renal circulation. After several
decades of research, “some means” are in reach, but not in the form
of a pill. However, some progress has been made towards a comprehensive
understanding of the mechanisms responsible for arteriogenesis.
Definitions
Arteriogenesis, formerly regarded as a variant of angiogenesis, is a
relatively new term that was introduced to distinguish it from other mechanisms
of vascular growth, such as angiogenesis and vasculogenesis [2]. Angiogenesis
describes the formation of new capillaries by sprouting and intussusception
from pre-existent capillaries, and vasculogenesis is the embryonic development
of blood vessels from angioblasts [3–5]. Arteriogenesis describes the
formation of mature arteries from pre-existent interconnecting arterioles after
an arterial occlusion. It shares some features with angiogenesis, but the
pathways leading to it are different, as are the final results: arteriogenesis
is potentially able to fully replace an occluded artery whereas angiogenesis
cannot. Under special circumstances, arteriogenesis may lead to the recovery of
markedly reduced blood flow. Increasing the number of capillaries within the
ischemic region cannot increase blood flow when its limiting structure lies
upstream. Another fundamental difference between the two types of vascular
growth is angiogenesis dependency on tissue hypoxia/ischemia, which leads to
the activation of the transcription factor HIF; in contrast, arteriogenesis
occurs in an environment of normoxia [6]. A collateral vessel, resulting from
the arteriogenic process, always conducts arterial blood flow and cannot, by
definition, become hypoxic. Collateral vessels in the vascular periphery are
surrounded by normoxic tissue even after acute femoral artery occlusion [6].
Collateral vessels: de-novo or pre-existent?
Controversy still exists as to whether mechanisms, such as the
recruitment of smooth muscle by capillaries or the attraction of smooth muscle
progenitor cells, which do not enlarge the pre-existent arteriolar networks
increase perfusion of ischemic tissue. Supporters of pre-existent arteriolar
networks argue that they can be demonstrated by a variety of techniques and
that they are present in the peripheral circulation of most mammals, including
humans. Since these well-defined vessels enlarge, the term arteriogenesis was
coined for them. During the early stages of collateral growth, many more
vessels are angiographically demonstrable in the vascular periphery, especially
in the rabbit and rat. These may have grown de-novo by the mechanisms cited
above. However, it remains possible that this vessel surplus reflects the fact
that smaller arterioles only become detectable after growth. Present
angiographic techniques can resolve vessels only to approximately 30 mm. Another
argument favoring pre-existent arterioles relates to the mouse (C57BL/6); it
has only six normally demonstrable interconnecting arterioles in the peripheral
circulation, and this number remains invariant after growth following femoral
occlusion. In rat, relatively large collateral can be detected with the naked
eye after contrast injection even without arterial occlusion. It is this
pre-existent vessel that enlarges upon femoral artery occlusion and carries
most of the collateral blood flow [7]. Also, Fulton showed that pre-existent
collaterals can be detected in the normal human heart and that those that
enlarge after coronary occlusion occupy the same topography [8]. The canine
heart relies completely on the pre-existent arteriolar network where the
shortest connections enlarge by growth. There is no evidence for angiogenesis
either within or outside the ischemic region. In contrast, observations from the heart of the domestic pig
challenge the importance of a pre-existent arteriolar network. The heart of the
domestic pig, unlike that of the dog, neither possesses an epicardial network
of arteriolar anastomoses nor develops arterial collateral vessels after slowly
progressing coronary stenosis. Rather it develops subendocardial giant
capillary networks devoid of smooth muscle. In addition, angiogenesis is
activated within the ischemic zone thereby reducing the anatomically defined
minimal resistance [9,10]. This means that the porcine heart relies almost
completely on angiogenesis as a defense mechanism following coronary artery occlusion
provided the speed of stenosis is very slow. The low intravascular pressure in
the porcine collateral circulation lowers the perfusion pressure gradient,
especially with high diastolic ventricular pressures (diastolic crunch), making
the myocardium highly susceptible to ischemia. In the vascular periphery, the
pig relies completely on pre-existent arteriolar connections (i.e. the response
to femoral artery occlusion is strictly arteriogenic). So this is not an
either-or question as both mechanisms may be present and active, though the
quantitative contribution of pre-existent arteriolar vessels is significantly
larger.
Physical Forces as Primary
Stimuli
It has been known for a long time that flow determines arterial size
and that pressure determines wall thickness (i.e. that form follows function).
Thoma [11], Schretzenmayr [12], Rodbard [13], Langille [14], Holtz [15], Tronc
[16] and Ben Driss [17] made the observation that arterial size depends on flow
during development, that adult arteries respond with structural changes to
changes in blood flow, and that lumen is controlled by ?n immediate physiological
adjustment in vascular tone induced by the change in flow, and a delayed
anatomical change that occurs when the change in flow persists [18–20]. Since these
studies, many have identified a host of molecules whose endothelial production
is also mediated by fluid shear stress (FSS) [18–20]. Recent studies by the
laboratories of Tedgui [21,22], Busse [23], Dejana [24] and from our own group
[25] have shed light on the mechanisms of transduction of the mechanical
stimulus into a growth response.FSS is proportional to blood flow velocity and inversely related to
the cube of the collateral vessel radius. Hence, increased blood flow directly results
in increased FSS. Since growth increases the collateral vessel radius, FSS
falls quickly; this may be the reason why arteriogenesis stops prematurely and
restores only 35%–40% of the maximal conductance of the replaced artery [26,27]. It
appears logical to increase FSS in order to improve the defective collateral
vessel growth. We recently developed a model where a state of high chronic FSS
was generated by shunting most of the collateral flow into the accompanying
vein thereby maintaining high collateral flow rates and high FSS levels. Under
these conditions, collateral conductance increased 4-fold compared with the
contra-lateral side, which was only occluded but not shunted. Under these
conditions, the maximal collateral conductance was already 100% at 7 d and had,
after 4 weeks, surpassed (2-fold) normal maximal conductance of the arterial
bed before occlusion [28]. Wall tension defined by pressure and radius [29] and
by pulsatile and cyclic stretch [23] were also discussed as activators of the endothelium
and, implicitly, as stimuli of vascular growth. However, immediately after
arterial occlusion, distal pressure falls, making wall stresses unlikely growth
stimuli. Likewise, pulsatile stretch of the arterial wall is low at low
pressure while the role of stretch-induced EDHF in vascular growth is unknown.
Maximal arteriogenesis occurs in situations at maximal flow (like in AV-shunts)
when pressure pulsations are minimal.FSS is proportional to blood flow velocity and inversely related to
the cube of the collateral vessel radius. Hence, increased blood flow directly results
in increased FSS. Since growth increases the collateral vessel radius, FSS
falls quickly; this may be the reason why arteriogenesis stops prematurely and
restores only 35%–40% of the maximal conductance of the replaced artery [26,27]. It
appears logical to increase FSS in order to improve the defective collateral
vessel growth. We recently developed a model where a state of high chronic FSS
was generated by shunting most of the collateral flow into the accompanying
vein thereby maintaining high collateral flow rates and high FSS levels. Under
these conditions, collateral conductance increased 4-fold compared with the
contra-lateral side, which was only occluded but not shunted. Under these
conditions, the maximal collateral conductance was already 100% at 7 d and had,
after 4 weeks, surpassed (2-fold) normal maximal conductance of the arterial
bed before occlusion [28]. Wall tension defined by pressure and radius [29] and
by pulsatile and cyclic stretch [23] were also discussed as activators of the endothelium
and, implicitly, as stimuli of vascular growth. However, immediately after
arterial occlusion, distal pressure falls, making wall stresses unlikely growth
stimuli. Likewise, pulsatile stretch of the arterial wall is low at low
pressure while the role of stretch-induced EDHF in vascular growth is unknown.
Maximal arteriogenesis occurs in situations at maximal flow (like in AV-shunts)
when pressure pulsations are minimal.
The Role of the Endothelium
Shortly after coronary occlusion, the endothelial cells of
collateral vessels appeared swollen and longitudinal bulges, as opposed to the
completely flat inner surface of small normal coronary arteries, appeared. The
cells are randomly oriented and do not longer line up in the direction of blood
flow. The activation of the endothelium was first reported by Schaper et al
who observed DNA synthesis with thymidine labeling in canine coronary
collateral arterioles subjected to progressive stenosis of the left circumflex
coronary artery [30,31]. Similar results were reported later with BrdU labeling
or the cell cycle-specific antibody Ki67 [32,33]. These activated endothelial
cells contain numerous cellular organelles, particularly free ribosomes in the
cytoplasm [34–36]. Activated endothelium also shows increased endothelial NO
synthetase (eNOS), monocyte chemoattractant protein (MCP-1), TGF-b, and the
adhesion molecules ICAM-1 and VCAM [36]. Consequently, increased permeability
of the endothelium, as indicated by the leakage of plasma proteins,
erythrocytes and platelets into the vascular wall and the adherence of
monocytes to the endothelium, were observed [34]. Activated endothelium also
changes the open probability of the calcium-dependent chloride channels, and
chloride channel inhibitors interfere with arteriogenesis [25,37]. A large
number of molecules involved in cell proliferation and migration were found to
be up-regulated. These include MMP-2, 9, t-PA, u-PA, FAK, integrin a5b1 and integrin
avb3 [38–40]. Most
recently bone marrow tyrosine kinase (Bmx; also called endothelial/epithelial
tyrosine kinase [41]), a FAK-activation molecule whose downstream effectors
involve cell migration, was reported to be highly induced in the endothelium
during ischemia-mediated arteriogenesis [41]. It is known that the evolutionary
conserved Notch signaling pathway is involved in vascular development [25,42–44]. Limbourg et
al recently showed that Notch ligand Delta-like 1 (Dll1) expression in
endothelium is strongly induced, and Notch signaling is activated and ephrin-B2
is up-regulated during arteriogenesis [45]. However, in Dll1 mutant mice after
hind limb ischemia, arterial collateral growth was abrogated and recovery of
blood flow was severely impaired, suggesting that Dll1 is essential for
postnatal arteriogenesis [25]. Ingber’s Tensegrity model [46] states that the
deformation of the endothelial cell by fluid shear stress, resulting in a
different distribution of force in the cytoskeleton, initiates gene
transcription and is an important part of the endothelial activation. However,
the cytoskeletal marker vimentin disappears completely from activated and
proliferating endothelium [47].
Smooth muscle cells
Smooth muscle carries most of the burden of arterioles’
transformation into collateral vessels. Vascular smooth muscle cells (VSMCs)
undergo the most drastic changes and increase their tissue mass depending on
the species; for example, it increases 3-fold in mice, 10-fold in rabbits,
20-fold in canines and even more in humans [25]. The remarkable plasticity of
the SMCs, particularly their ability to change phenotype from the contractile
to the synthetic, in response to stimuli from environmental cues [48–51] makes this
possible. VSMC proliferation, phenotypic changes and the occurrence of a
neointima are typical for arteriogenesis [29,32,34,39]. Coronary collaterals
show two zones of growth: a very active neointima consisting mostly of
synthetic-type SMC and a media with somewhat less active SMC [25]. Although the
filamentous a-smooth muscle actin had almost completely disappeared in the
synthetic phenotype, depolymerized actin is still present in abundance. Desmin,
one of the principal intermediate filament proteins in VSMC, is a marker for
contractile SMC, but it disappears during active growth of the synthetic SMC. Similar
data were reported by Buus et al in flow-related remodeling of rat
mesenteric resistance arteries where there was reduced expression of desmin in
VSMC [25]. Therefore, the absence of desmin in the SMC of the neointima makes
it a marker for the active phase of arteriogenesis [52]. Vinculin, a cytoskeleton-associated protein that links the
extracellular matrix and the intracellular milieu via integrins, almost
completely disappears from both layers, possibly enabling the mobilization of
SMC. Furthermore, proteolytic MMP-2 and MMP-9 are very active in both layers,
but their inhibitor TIMP-1 is only expressed in the tunica media. Mobilization
of SMC is facilitated by lysis of extracellular matrix proteins. PAI-1 is
overexpressed in the neointima as well as in the media and does not entirely
normalize during vessel maturation.The regression of the neointima in the canine coronary system takes
several months. However, in some mature collateral vessels, the neointima grows
excessively by proliferating SMC until the vessel is completely obliterated.
This process is called “pruning” and results in a reduction of the
high number of small collateral vessels in favor of a few large ones [25]. The degradation of BM, IEL and EEL by proteolysis mobilizes SMC.
This is also facilitated by other proteins, such as the non-receptor tyrosin
kinase FAK, integrins a5b1 and avb3, and Erk1/2. FAK is a cytoplasmic protein-tyrosine kinase that
localizes to focal contacts and adhesions. It triggers intracellular signals
promoting cell migration [53] by reacting to extracellular matrix-integrin and
growth factor stimulation. The involvement of FAK in blood vessel
morphogenesis, SMC proliferation, phenotype change, migration and intimal
hyperplasia was documented in several recent articles [54–59]. Mechanical
strain, growth factor stimulation and shear stress in collateral vessels lead
to autophosporylation of FAK/ERK and to migration and proliferation of VSMC
[28,60,61]. FAK localizes where cells interact with the extracellular matrix
through integrin receptors. avb3, which was shown to mediate SMC accumulation in the neointima in
ligated carotid arteries in mice [62] was also strongly overexpressed in the
neointima of collateral vessels [35]. Integrin clustering upon binding to extracellular
matrix components, such as fibronectin, results in activation of FAK [63].Integrin a5b1 is mainly a fibronectin-receptor. It mediates most of
fibronectin’s biological activities. Integrin a5b1, stimulated by soluble
or anchored fibronectin, promotes cellular locomotion [64]. Integrin a5b1 and
fibronectin [32] are markedly increased in growing collateral vessels and may
play an important role in SMC mobility and signal transduction [39].
Smooth muscle lineage
The remarkable phenotypic plasticity of vascular smooth muscle and
its ability to re-enter the cell cycle raise the question of lineage,
especially when morphological markers are no longer helpful. During embryonic
development, SMC arise in multiple regions from different precursor
populations; specifically, the large vessels in the vascular periphery are
derived from mesenchymal neural crest cells, whereas the coronary arteries are
of non-neural crest origin [65]. It is of note that coronary collaterals differ
from those in the vascular periphery because of their tendency to form a
neointima with the ability to later regress or to continue proliferating
finally leading to occlusion (i.e. pruning). The clinical counterpart for this
is re-stenosis after stent placement. During development all muscle types share
some common markers, some of which are shed in later stages and some of which
are retained, such as calponin and SM22 in vascular smooth muscle [65,66].
These markers do not disappear during collateral vessel growth, which means
that invading cells have not trans-differentiated. Some of the embryonal common
markers, such as CARP and abra in both cardiac and in smooth muscle of
collateral vessels, are re-expressed under stressful conditions. SMC of collateral
vessels begin the S-phase of the cell cycle when still fully differentiated and
change phenotype only shortly before M-phase, which supports the argument that
collateral vessels grow by proliferation of cells in situ and do not
require cells of a different lineage. Connexin 37, an endothelial marker of the
embryonal arterial system that is down-regulated after birth, is re-expressed
in smooth muscle of growing collateral vessels, suggesting a re-capitulation of
the developmental pattern of gene expression as the basis of arteriogenesis
[67,68].
Extracellular Proteolysis and
Antiproteolysis
Proteolysis of the internal and external elastic lamina and of the
basement membranes [69–72] is necessary to overcome the structural barriers to growth. Early
in collateral vessel growth, the process is up-regulated and activates MMP-2,
MMP-9 and urokinase-type plasminogen activator (u-PA). As a consequence, the
IEL, the EEL and the BM become fragmented [39,47]. The controlled destruction
of the vascular scaffolding paves the way for the expansion and outward growth
of collateral vessels. Moreover, apoptosis of SMC may facilitate the renewal of
the vascular wall [32]. Since laminin and collagen IV promote the
differentiation and inhibit proliferation of SMC, the degradation of the BM may
also facilitate the shift of SMC phenotypes. Elastin is essential for arterial
morphogenesis [73,74]. Degradation of elastic fibers may contribute to the
proliferation and migration of VSMC. This has been supported by our experiments
with heterozygous elastin knockout mice that showed an accelerated recovery of
blood flow after femoral artery occlusion (Schaper et al, unpublished
data).
Bone Marrow-derived Cells
Between 1 d and 3 d after complete coronary occlusion following a
few weeks of progressive narrowing, Schaper et al observed massive
adhesion of monocytes to the endothelial lining of coronary collaterals [35].
The endothelial cells had lost spatial orientation as well as osmotic control;
this coincided with monocyte adhesion. Days later, monocytes as well as
lymphocytes, mast cells and leucocytes invaded the perivascular space. To test
whether these inflammatory reactions were important to the arteriogenic
process, anti-inflammatory treatment was applied; this treatment indicated that
collateral vessel growth indeed depends on an inflammatory environment [29].
Polverini et al also [75] showed that monocytes have angiogenic
properties. Decades later, it was shown that activated endothelium produced
MCP-1 and resulted in adhesion molecules appearing on the endothelial surface
[35]. The causal relationship was ascertained by showing that targeted
disruption of the MCP-1 gene and its cognate receptor, CCR-2, markedly
impairs arteriogenesis in an ischemic mouse hind limb experiment [25,76,77].
Neutralizing antibodies against ICAM-1 as well as an infusion of free ICAM-1
that neutralized the Mac-1 receptor on circulating monocytes both markedly
impaired the arteriogenic process. Deletion of monocytes by chemical bone
marrow suppression or by liposomes loaded with phosphonates that killed
monocytes/macrophages also inhibited collateral vessel formation [25]. After
femoral artery occlusion during the post-chemotherapy rebound and a transfusion
of an excess of monocytes, the monocyte population increased and accelerated
arteriogenesis. Furthermore, animals with hereditary monocytopenia (i.e. op/op
mice and osteopetrotic rats) showed only a stunted collateral response to
femoral artery occlusion. These experiments clearly established the causal
relationship between monocytes and the arteriogenic process [78]. Other bone marrow-derived cells, in particular lymphocytes of the NK
type and CD-4 and CD-8 cells, also play a role [79,80]. Their importance became
known when the marked difference in response to femoral artery occlusion
between mouse strains was observed. “Black” mice (C75BL/6) tolerated
the occlusion much better than “white” mice (BALB/c). They showed a
slightly higher residual blood flow immediately after femoral occlusion, they
exhibited almost no toe necroses and their blood flow recovery was complete
after only one week. In contrast, self-amputated toes were frequent in the
white mice and their blood flow recovery was slow and incomplete. The basic
difference between these strains is their immune systems. Black mice are
specially bred for studies concerning the T-cell receptors and show an
abundance of NK cells. When antibodies or genetic manipulation eliminate these
cells, black mice lose their advantage. However, the genetic trait is dominant
and the F1 generation of black/white crosses still enjoys the ischemia
resistance. Hematopoietic stem cells (rather than differentiated mononuclear
white cells) were reported to be metaplastic and, when attaching to collateral
vessels, transform into endothelial and smooth muscle cells. Detailed laser
confocal studies showed that BM-derived cells from GFP-transplanted bone marrow
neither incorporated into the wall of collateral arteries nor exhibited the
endothelial or smooth muscle phenotype [81]. Since BM-derived cells secrete a
wide array of cytokines, such as bFGF and VEGF, it is suggested that they
contribute to collateral remodeling through paracrine mechanisms [27]. Recently
the role of BM-derived mesenchymal stem cells in arteriogenesis was
investigated in rat and swine acute myocardial infarction [82–84]. Though the
arteriogenic data were controversial, these experiments confirmed improved
heart function. Martens et al showed induction of vascular network
formation and arteriogenesis [82], but Yang et al did not detect growth
of collateral arteries [84]. Whether these results varied due to species
differences therefore remains an open question.
Activation of the adventitia
In normal small arterioles, the adventitia is a small rim composed
primarily of a few fibroblasts, collagen, elastin fibers and other ECM
materials, which form the barrier between the adventitia and the media. In
growing collateral vessels the adventitia undergoes drastic changes. An early
study showed that an acute inflammatory reaction was present in the adventitia
of collateral vessels in canine heart [85]. Later experiments in rabbit and rat
hind limbs confirmed these findings by showing an accumulation of macrophages
in the adventitia. Adhesion molecules, like VCAM, may account for this
inflammatory process since they were dramatically up-regulated in the
adventitia [86]. As a consequence, macrophages and activated fibroblasts
produce growth factors and MMPs [87,88], contributing to the enlargement of
collateral vessels. At present, the role of mast cells that are also present in
much higher than normal numbers around growing collateral vessels is unclear
[32]. Targeted disruption of the mast cell growth factor in mice increased the
recovery of the ischemic hind limb after femoral artery occlusion, measured by
TOF magnetic resonance imaging, indicating a restraining influence of mast
cells on vascular growth [25].
Collateral vessels in various
vascular provinces
In the coronary system, monocytes adhere initially to the
endothelial surface and invade the intima. The perivascular space later becomes
populated with white cells, which provide space for the expanding collateral
vessels by destroying and removing tissue that is in the way. In the vascular
periphery, only a few monocytes adhere to the shear stressed endothelium, and
leaky post-capillary venules may have made the marked invasion of the
perivascular space possible. This may be due to the expression of VEGF, which
primarily increases permeability. Another difference is that the neointima is
not as well developed in the vascular periphery, especially in the mouse hind
leg.
The Enigma of
NO
The role of NO in arteriogenesis remains unclear because collateral
artery growth is totally dependent on mitosis, and NO is a known anti-mitogen
[25]. Even when taking into account that NO stimulates VEGF release, a
plausible explanation of NO’s role has not emerged because VEGF is not a known
mitogen for SMC, the dominant cell type in arteriogenesis. The enigmatic role
of NO is highlighted by the fact that mice with targeted disruption of the
eNOS gene have had retarded recovery of blood flow following femoral artery
occlusion, which is indicative at first sight of defective arteriogenesis.
However, morphometric analysis of collateral vessels has shown them to be of
normal caliber and number, and the application of NO donors has restored blood
flow to levels identical to those of wild-type mice [25,89]. This indicates
that the growth of collateral vessels was not impaired [25], and that retarded
recovery was only apparent, dominated by vasoconstriction. Femoral artery
occlusion in transgenic eNOS overexpressing mice showed normal recovery of
blood flow after femoral occlusion and the time course of recovery, and its
final extent did not differ from that of wild-type mice [89]. These experiments
would allow only one explanation, namely that eNOS-produced NO plays no role in
arteriogenesis. However, the effects of maximally FSS-stimulated collateral
artery growth in rabbits were totally reversed by the application of the NOS
inhibitor L-NAME [28]. In addition, application of L-NAME also impaired
exercise improved collateral-dependent blood flow in rats [90,91].This was
difficult to reconcile with the mouse experiments. Since L-NAME is rather
non-specific and also inhibits also iNOS, we hypothesize that L-NAME’s strong
inhibitory effects inactivated the monocytes/macrophages (carriers of iNOS)
essential to collateral vessel growth. Therefore, we conclude that NO plays a
crucial role in arteriogenesis as a tool of the monocytes/macrophages whose
function is dependent on the activity of iNOS. NO donors, other than eNOS, may
have aided in collateral growth in the eNOS-targeted mice.
Is neural regulation a
contributor to arteriogenesis?
An increasing body of evidence suggests that during development
nerve fibers and blood vessels share common signaling cues, including Netrins,
Slits, Ephrins, Neuropilins and Semaphorins [92–94]. Mukouyama et al
reported that arteries, but not veins, are specifically aligned with peripheral
nerves in embryonic mouse limb skin. Elimination of peripheral sensory nerves,
or Schwann cells, by Neurogenin1/Neurogenin2 double homozygous knockouts results
in defective arteriogenesis. Disorganization of the peripheral nerves by a
mutation in the Semaphorin3A gene maintains the alignment of arteries
with misrouted axons, indicating that nerves direct vascular remodeling
patterns and arteriogenesis [95]. It is well known that the nerves that modulate blood vessel function
release many kinds of neuropeptides, including secretoneurin, substance P,
neuropeptide Y and calcitonin gene-related peptide. These neuropeptides have
the ability to stimulate endothelial cell, fibroblast and SMC migration and
proliferation in vitro [96–99]. These neuropeptides have also been shown
to be involved in mediating the inflammatory process by enhancing the
expression of adhesion molecules, such as VECAM [100,101]. They increase
arteriolar density and branching when overexpressed in the heart [102], and
attract monocytes, eosinophils and endothelial cells [103,104]. Recently these
neuropeptides were reported to exhibit direct angiogenic properties stimulating
neo-vascularization and inducing postnatal vasculogenesis [105,106], and to
restore ischemic muscle blood flow and performance [107]. Taken together, these
results suggest that neural regulation may be involved in collateral vessel
growth.
The Role of
Growth Factors
The occurrence of mitosis in both the endothelial and smooth muscle
cells of collateral vessels indicates the presence of mitogens. However, none
of the well-known growth factors like VEGF, FGF, PDGF etc, could be unanimously
identified as being involved as a “master” factor. VEGF-A protein is
up-regulated in shear-stressed endothelium, and may enable endothelial mitosis
and increased vascular permeability leading to regularly observed perivascular
edema [81,108]. Although the VEGF receptor 2 is identifiable on the endothelial
surface and could hence be responsible for endothelial mitosis and inactivation
of this receptor inhibited arteriogenesis in rats [109], it is present as a
protein complex sensing shear stress [24]. However, its up-regulation takes place
when most of the mitotic activity is already over. The FGF receptor-1 is
present in the collateral tissue, but arteriogenesis proceeds undisturbed in
mice with targeted disruption of the FGF-1 and FGF-2 genes and in
double knockouts [110]. Overexpression of FGF-2 in skeletal muscle does not
accelerate arteriogenesis [25]. In contrast, PSA, a chemical agent that
interferes with FGF-receptor binding, inhibits arteriogenesis in the rabbit
hind limb model [111].All mentioned growth factors accelerate collateral artery growth
when exogenously applied, but blood flow recovery never reaches the levels
obtained with high shear stress. Arteriogenic mitogens may be the actin-binding
proteins Abra and Thymosin beta 4 [112]. Although these are intracellular
proteins without hints from their sequence for secretion, they have mitogenic
potency for SMC when applied to cells in culture. They share the absence of
secretion motifs with FGF-1 and FGF-2. Furthermore, it is not clear to what
kind of receptor they may bind to. Therefore, the mitogens responsible for the natural process of
arteriogenesis remain undiscovered.
Arteriogenic pathways and
signal transduction
Several signaling cascades have to converge to form a new artery to
defend against tissue ischemia caused by arterial obstruction (Fig. 1).
At least two pathways originate at the flow/shear stressed endothelium: (1) the
attraction, adhesion and invasion of bone marrow-derived cells that are needed
for structural remodeling and (2) the pathway for endothelial and smooth muscle
cell proliferation. The primary signal in response to shear stress is NO
followed by expression of a protein complex consisting of E-cadherin, VEGFR2
and PECAM plus several transcription factors, such as CARP and klf2, whose
precise function is not well known. NO leads to the production of VEGF that,
together with calcium-activated ion channels, interferes with osmotic
regulation of the endothelium. This leads to the synthetic phenotype of
endothelial cells and the production of chemokines, such as MCP-1. The smooth
muscle of the media likewise undergoes a phenotype change and enters the cell
cycle. In preparation for mitosis, actin-binding proteins, such as abra and
thymosin b4, play an important role, and the Rho pathway becomes activated. Arteriogenesis
is inhibited by fasudil, a Rho-pathway inhibitor. Studies with cultured VSMC
exposed to FGF-2 or PDGF showed activation of signaling cascades that were
similarly observed in collateral vessel tissue that had developed after
arterial occlusion under the influence of shear forces (fig. 2). This comprised in
particular the Ras/MEK/ERK pathway, the down-regulation of desmin, the
polymerization of actin, up-regulation of the transcription factors CARP, SRE
and EGR-1 [25]. The similarity between the in vivo and in vitro
responses suggests the presence of similar growth factors, perhaps with the
exception of PDGF because protein kinase B is down-regulated under conditions
of high fluid shear stress. In contrast, neither targeted disruption nor
transgenic overexpression of FGF-1 and FGF-2 influence arteriogenesis probably
because other members of the FGF family of growth factors are able to
substitute. We have anecdotal evidence that the triple knockout of FGF-5, 6 and
7 markedly inhibits arteriogenesis (the animals were a kind gift of Dr. E.
Bober, Max-Planck-Institute, Bad Nauheim).It is of note that EGR-1 is up-regulated in the endothelium by shear
stress via NO and in cultured SMC by FGF-2 and PDGF-AB [110]. This emphasizes
the fact that we lack a clear understanding of how the shear stress signal is
transmitted from the endothelium to the smooth muscle layer in the absence of
cell-to-cell junctions, with the barrier of the internal elastic lamina and
with the short reach of the highly reactive radical NO.The importance of the MEK/ERK pathway is highlighted by the
inhibition of smooth muscle mitosis after treatment with the MEK antagonists
UO126 and PD98059. These antagonists induce hyper-phosphorylation at serine
217/221, which might act as an on/off switch depending on context (Fig. 2)
Pharmacological inhibition of NOS blocks the FSS-cascade regardless of the
isoform. Blockade of bone marrow-derived cells also markedly inhibits
arteriogenesis.
Summary
Under favorable conditions (e.g. slowly progressing coronary
occlusion), arteriogenesis is able to salvage tissue through the rapid growth
of collateral vessels. In the vascular periphery, even acute occlusions are
tolerated and full function may return within days or weeks due to collateral
development. Understanding of the molecular mechanisms has progressed in recent
years, but one important step is still not well understood: how forces acting
on the endothelium are transmitted to the smooth muscular tunica media. Under
the influence of pressure gradients that occur after arterial occlusions, blood
flow in pre-existent arteriolar connections is increased and, with it fluid
shear stress transforms these vascular structures into arteries that are
potentially able to replace the occluded vessel. The tissue surrounding growing
collateral vessels does not become ischemic, and arteriogenesis does not depend
on tissue oxygenation. High fluid shear stress activates ion channels, releases
NO and starts at least two signaling pathways: one that attracts bone
marrow-derived cells for remodeling and another that causes endothelial and
smooth muscle cells to enter the cell cycle, leading to proliferation. The
transformation of a small arteriole into a large blood flow transporter
proceeds by controlled destruction of the old structure by digestion of the
elastic scaffold and apoptosis of non-mitotic SMC. As producers of mitogens and
proteases, invading monocytes and lymphocytes are crucial for the
transformation. The role of angiogenic growth factors remains unsolved, and
arteriogenesis differs in this aspect and in several others from angiogenesis.
Signaling pathways for arteriogenesis involve the MAPKinases, the Rho-pathway
and NO-dependent pathways. The latter two may be worth studying to design
stimulators of arteriogenesis.
References
1 Fulton WF. The
morphology of coronary arterial anastomoses in health and disease and their
influence on ischaemic myocardial damage. Acta Cardiol 1969, 12: 38–67
2 Schaper W, Buschmann
I. Arteriogenesis, the good and bad of it. Cardiovasc Res 1999, 43: 835–837
3 Risau W, Flamme I.
Vasculogenesis. Annu Rev Cell Dev Biol 1995, 11: 73–91
4 Patan S, Haenni B,
Burri PH. Implementation of intussusceptive microvascular growth in the chicken
chorioallantoic membrane (CAM): 1. pillar formation by folding of the capillary
wall. Microvasc Res 1996, 51: 80–98
5 Folkman J.
Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov
2007, 6: 273–286
6 Helisch A, Wagner S,
Khan N, Drinane M, Wolfram S, Heil M. Impact of mouse strain differences in
innate hindlimb collateral vasculature. Arterioscler Thromb Vasc Biol 2006 Mar;
26: 520–526
7 Ito WD, Arras M, Scholz
D, Winkler B, Htun P, Schaper W. Angiogenesis but not collateral growth is
associated with ischemia after femoral artery occlusion. Am J Physiol 1997;
273: H1255-H1265.
8 Fulton WF.
Anastomotic enlargement and ischemic myocardial damage. Br Heart J 1964, 26: 1–15
9 Roth DM, Maruoka
Y, Rogers J, White FC, Longhurst JC, Bloor CM. Development of coronary
collateral circulation in left circumflex ameroid-occluded swine myocardium. Am
J Physiol 1987, 253: H1279–H1288
10 Bloor CM, White FC,
Sanders TM. Effects of exercise on collateral development in myocardial
ischemia in pigs. J Appl Physiol 1984, 56: 656–665
11 Thoma R. Untersuchungen
fiber die Histogenese und ttistomechanik des GefBsystems. Stuttgart: Enke, 1893
12 Schretzenmeyr A. ?ber
kreislaufregulatorische Vorg?nge bei Muskelarbeit. Pfluger’s Arch Gesamte
Physiol Menschen Tiere 1933, 232: 743–748
13 Rodbard S. Vascular
caliber. Cardiology 1975, 60: 4–49
14 Langille BL. Remodeling
of developing and mature arteries: endothelium, smooth muscle, and matrix. J
Cardiovasc Pharmacol 1993, 21: S11–S17
15 Holtz J, Pohl U, Giesler
M, Bassenge E. Flow-dependent, endothelium-mediated dilation of epicardial
coronary arteries in conscious dogs: effects of cyclooxygenase inhibition. J
Cardiovasc Pharmacol 1984, 6: 1161–1169
16 Tronc F, Wassef M,
Esposito B, Henrion D, Glagov S, Tedgui A. Role of NO in flow-induced
remodeling of the rabbit common carotid artery. Arterioscler Thromb Vasc Biol
1996, 16: 1256-1262
17 Ben Driss A, Benessiano
J, Poitevin P, Levy BI, Michel JB. Arterial expansive remodeling induced by
high flow rates. Am J Physiol 1997, 272: H851–H858
18 Papadaki M, Eskin SG,
Ruef J, Runge MS, McIntire LV. Fluid shear stress as a regulator of gene
expression in vascular cells: possible correlations with diabetic
abnormalities. Diabetes Res Clin Pract 1999, 45: 89–99
19 Davies PF. Flow-mediated
endothelial mechanotransduction. Physiol Review 1995, 75: 519–560
20 Resnick N, Gimbrone MA
Jr. Hemodynamic forces are complex regulators of endothelial gene expression.
FASEB J 1995, 9: 874–882
21 Castier Y, Brandes RP,
Leseche G, Tedgui A, Lehoux S. p47phox-dependent NADPH oxidase regulates
flow-induced vascular remodeling. Circ Res 2005, 97: 533–540
22 Lehoux S, Tedgui A.
Making up and breaking up: the tortuous ways of the vascular wall. Arterioscler
Thromb Vasc Biol 2005, 25: 892–894
23 Busse R, Fleming I.
Pulsatile stretch and shear stress: physical stimuli determining the production
of endothelium-derived relaxing factors. J Vasc Res 1998, 35: 73–84
24 Tzima E, Irani-Tehrani
M, Kiosses WB, Dejana E, Schultz DA, Engelhardt B, Cao G et al. A
mechanosensory complex that mediates the endothelial cell response to fluid
shear stress. Nature 2005, 437: 426–431
25 Schaper W, Schaper J.
Arteriogenesis. London: Kluwer Academics Publisher 2004
26 Schaper W, Flameng W,
Winkler B, Wuesten B, T?rschmann W, Neugebauer G, Carl M et al.
Quantification of collateral resistance in acute and chronic experimental
coronary occlusion in the dog. Circ Res 1976, 39: 371–377
27 Kinnaird T, Stabile E,
Burnett MS, Shou M, Lee CW, Barr S, Fuchs S et al. Local delivery of
marrow-derived stromal cells augments collateral perfusion through paracrine
mechanisms. Circulation 2004, 109: 1543–1549
28 Eitenmuller I, Volger O,
Kluge A, Troidl K, Barancik M, Cai WJ, Heil M et al. The range of
adaptation by collateral vessels after femoral artery occlusion. Circ Res 2006,
99: 656–662
29 Schaper W. The
Collateral Circulation of the Heart. Amsterdam: Elsevier North Holland
Publishing Company, 1971
30 Pasyk S, Schaper W,
Schaper J, Pasyk K, Miskiewicz G, Steinseifer B. DNA synthesis in coronary
collaterals after coronary artery occlusion in conscious dog. Am J Physiol
1982, 242: H1031–H1037
31 Schaper W, De Brabander
M, Lewi P. DNA synthesis and mitoses in coronary collateral vessels of the dog.
Circ Res 1971, 28: 671–679
32 Wolf C, Cai WJ,
Vosschulte R, Koltai S, Mousavipour D, Scholz D, Afsah-Hedjri A et al.
Vascular remodeling and altered protein expression during growth of coronary collateral
arteries. J Mol Cell Cardiol 1998, 30: 2291–2305
33 Arras M, Strasser R,
Mohri M, Doll R, Eckert P, Schaper W, Schaper J. Tumor necrosis factor-alpha is
expressed by monocytes/macrophages following cardiac microembolization and is
antagonized by cyclosporine. Basic Res Cardiol 1998, 93: 97–107
34 Schaper J, Borgers M,
Schaper W. Ultrastructure of ischemia-induced changes in the precapillary
anastomotic network of the heart. Am J Cardiol 1972, 29: 851–859
35 Schaper J, Konig R, Franz
D, Schaper W. The endothelial surface of growing coronary collateral arteries.
Intimal margination and diapedesis of monocytes. A combined SEM and TEM study.
Virchows Arch A Pathol Anat Histol 1976, 370: 193–205
36 Scholz D, Ito W, Fleming
I, Deindl E, Sauer A, Wiesnet M, Busse R et al. Ultrastructure and
molecular histology of rabbit hind-limb collateral artery growth
(arteriogenesis). Virchows Arch 2000, 436: 257–270
37 Voets T, Szucs G,
Droogmans G, Nilius B. Blockers of volume-activated Cl- currents inhibit
endothelial cell proliferation. Pflugers Arch 1995, 431: 132–134
38 Tyagi SC, Kumar S,
Cassatt S, Parker JL. Temporal expression of extracellular matrix
metalloproteinases and tissue plasminogen activator in the development of
collateral vessels in the canine model of coronary occlusion. Can J Physiol
Pharmacol 1996, 74: 983–995
39 Cai W, Vosschulte R,
Afsah-Hedjri A, Koltai S, Kocsis E, Scholz D, Kostin S et al. Altered
balance between extracellular proteolysis and antiproteolysis is associated
with adaptive coronary arteriogenesis. J Mol Cell Cardiol 2000, 32: 997–1011
40 Haas TL, Doyle JL,
Distasi MR, Norton LE, Sheridan KM, Unthank JL. Involvement of MMPs in the
outward remodeling of collateral mesenteric arteries. Am J Physiol Heart Circ
Physiol 2007, 293: H2429–H2437
41 He Y, Luo Y, Tang S,
Rajantie I, Salven P, Heil M. Critical function of Bmx/Etk in ischemia-mediated
arteriogenesis and angiogenesis. J Clin Invest 2006, 116: 2344–2355
42 Lawson ND, Vogel AM,
Weinstein BM. sonic hedgehog and vascular endothelial growth factor act
upstream of the Notch pathway during arterial endothelial differentiation. Dev
Cell 2002, 3: 127–136
43 Shawber CJ, Kitajewski
J. Notch function in the vasculature: insights from zebrafish, mouse and man.
Bioessays 2004, 26: 225–234
44 Gridley T. Notch
signaling during vascular development. Proc Natl Acad Sci USA 2001, 98: 5377–5378
45 Limbourg A, Ploom M,
Elligsen D, S?rensen I, Ziegelhoeffer T, Gossler A, Drexler H et al.
Notch ligand Delta-like 1 is essential for postnatal arteriogenesis. Circ Res
2007, 100: 363–371
46 Ingber DE. Tensegrity I.
Cell structure and hierarchical systems biology. J Cell Sci 2003, 116: 1157–1173
47 Cai WJ, Kocsis E, Wu X,
Rodriguez M, Luo X, Schaper W. Remodeling of the vascular tunica media is
essential for development of collateral vessels in the canine heart. Mol Cell
Biochem 2004, 264: 201–210
48 Glukhova MA, Kabakov AE,
Frid MG, Ornatsky OI, Belkin AM, Mukhin DN. Modulation of human aorta smooth
muscle cell phenotype: a study of muscle-specific variants of vinculin,
caldesmon, and actin expression. Proc Natl Acad Sci USA 1988, 85: 9542–9546
49 Mosse PR, Campbell GR,
Campbell JH. Smooth muscle phenotypic expression in human carotid arteries. II.
Atherosclerosis-free diffuse intimal thickenings compared with the media.
Arteriosclerosis 1986, 6: 664–669
50 Giuriato L, Scatena M,
Chiavegato A, Zanellato AM, Guidolin D, Pauletto P. Localization and smooth
muscle cell composition of atherosclerotic lesions in Watanabe heritable
hyperlipidemic rabbits. Arterioscler Thromb 1993, 13: 347–359
51 Kocher O, Gabbiani F,
Gabbiani G, Reidy MA, Cokay MS, Peters H. Phenotypic features of smooth muscle
cells during the evolution of experimental carotid artery intimal thickening.
Biochemical and morphologic studies. Lab Invest 1991, 65: 459–470
52 Cai WJ, Kocsis E, Scholz
D, Luo X, Schaper W, Schaper J. Presence of Cx37 and lack of desmin in smooth
muscle cells are early markers for arteriogenesis. Mol Cell Biochem 2004, 262:
17–23
53 Sieg DJ, Hauck CR,
Schlaepfer DD. Required role of focal adhesion kinase (FAK) for
integrin-stimulated cell migration. J Cell Sci 1999, 112: 2677–2691
54 Morla AO, Mogford JE.
Control of smooth muscle cell proliferation and phenotype by integrin signaling
through focal adhesion kinase. Biochem Biophys Res Commun 2000, 272: 298–302
55 Ilic D, Kovacic B,
Johkura K, Schlaepfer DD, Tomasevic N, Han Q. FAK promotes organization of
fibronectin matrix and fibrillar adhesions. J Cell Sci 2004, 117: 177–187
56 Ilic D, Kovacic B,
McDonagh S, Jin F, Baumbusch C, Gardner DG. Focal adhesion kinase is required
for blood vessel morphogenesis. Circ Res 2003, 92: 300–307
57 Owens LV, Xu L, Marston
WA, Yang X, Farber MA, Iacocca MV. Overexpression of the focal adhesion kinase
(p125FAK) in the vascular smooth muscle cells of intimal hyperplasia. J Vasc
Surg 2001, 34: 344–349
58 Taylor JM, Mack CP,
Nolan K, Regan CP, Owens GK, Parsons JT. Selective expression of an endogenous
inhibitor of FAK regulates proliferation and migration of vascular smooth
muscle cells. Mol Cell Biol 2001, 21: 1565–1572
59 Hauck CR, Sieg DJ, Hsia
DA, Loftus JC, Gaarde WA, Monia BP. Inhibition of focal adhesion kinase
expression or activity disrupts epidermal growth factor-stimulated signaling
promoting the migration of invasive human carcinoma cells. Cancer Res 2001, 61:
7079–7090
60 Boutahar N, Guignandon
A, Vico L, Lafage-Proust MH. Mechanical strain on osteoblasts activates
autophosphorylation of focal adhesion kinase and proline-rich tyrosine kinase 2
tyrosine sites involved in ERK activation. J Biol Chem 2004, 279: 30588–30599
61 Ma H, Calderon TM,
Kessel T, Ashton AW, Berman JW. Mechanisms of hepatocyte growth factor-mediated
vascular smooth muscle cell migration. Circ Res 2003, 93: 1066–1073
62 Choi ET, Khan MF,
Leidenfrost JE, Collins ET, Boc KP, Villa BR. Beta3-integrin mediates smooth
muscle cell accumulation in neointima after carotid ligation in mice.
Circulation 2004, 109: 1564–1569
63 Schlaepfer DD, Hauck CR,
Sieg DJ. Signaling through focal adhesion kinase. Prog Biophys Mol Biol 1999,
71: 435–478
64 Zetter BR, Brightman SE.
Cell motility and the extracellular matrix. Curr Opin Cell Biol 1990, 2: 850–856
65 Li L, Miano JM, Cserjesi
P, Olson EN. SM22 alpha, a marker of adult smooth muscle, is expressed in
multiple myogenic lineages during embryogenesis. Circ Res 1996, 78: 188–195
66 Yoshida T, Owens GK.
Molecular determinants of vascular smooth muscle cell diversity. Circ Res 2005,
96: 280–291
67 Delorme B, Dahl E,
Jarry-Guichard T, Briand JP, Willecke K, Gros D. Expression pattern of connexin
gene products at the early developmental stages of the mouse cardiovascular
system. Circ Res 1997, 81: 423–437
68 Rummery NM, Hickey H,
McGurk G, Hill CE. Connexin37 is the major connexin expressed in the media of
caudal artery. Arterioscler Thromb Vasc Biol 2002, 22: 1427–1432
69 Hedin U, Bottger BA,
Forsberg E, Johansson S, Thyberg J. Diverse effects of fibronectin and laminin
on phenotypic properties of cultured arterial smooth muscle cells. J Cell Biol
1988, 107: 307-319
70 Hedin U, Bottger BA,
Luthman J, Johansson S, Thyberg J. A substrate of the cell-attachment sequence
of fibronectin (Arg-Gly-Asp-Ser) is sufficient to promote transition of
arterial smooth muscle cells from a contractile to a synthetic phenotype. Dev
Biol 1989, 133: 489–501
71 Thyberg J.
Differentiated properties and proliferation of arterial smooth muscle cells in
culture. Int Rev Cytol 1996, 169: 183–265
72 Palmberg L, Claesson HE,
Thyberg J. Effects of leukotrienes on phenotypic properties and growth of
arterial smooth muscle cells in primary culture. J Cell Sci 1989, 93: 403–408
73 Li DY, Brooke B, Davis
EC, Mecham RP, Sorensen LK, Boak BB. Elastin is an essential determinant of
arterial morphogenesis. Nature 1998, 393: 276–280
74 Karnik SK, Brooke BS,
Bayes-Genis A, Sorensen L, Wythe JD, Schwartz RS. A critical role for elastin
signaling in vascular morphogenesis and disease. Development 2003, 130: 411–423
75 Polverini PJ, Cotran RS,
Gimbrone MA, Unanue EM. Activated macrophages induce vascular proliferation.
Nature 1977, 269: 804–806
76 Pipp F, Heil M,
Issbrucker K, Ziegelhoeffer T, Martin S, van den Heuvel J. VEGFR-1-selective
VEGF homologue PlGF is arteriogenic: evidence for a monocyte-mediated
mechanism. Circ Res 2003, 92: 378–385
77 Clauss M, Pipp F,
Issbr?cker K, Weich H, Heil M, Schaper W. Dissection of monocyte and
endothelial activities by using VEGF-receptor specific ligands. Adv Exp Med
Biol 2003, 522: 75–82
78 Bergmann CE, Hoefer IE,
Meder B, Roth H, van Royen N, Breit SM. Arteriogenesis depends on circulating
monocytes and macrophage accumulation and is severely depressed in op/op mice.
J Leukoc Biol 2006, 80: 59–65
79 van Weel V, Toes RE,
Seghers L, Deckers MM, de Vries MR, Eilers PH. Natural killer cells and CD4+
T-cells modulate collateral artery development. Arterioscler Thromb Vasc Biol
2007, 27: 2310–2318
80 Stabile E, Kinnaird T,
la Sala A, Hanson SK, Watkins C, Campia U. CD8+ T lymphocytes regulate the
arteriogenic response to ischemia by infiltrating the site of collateral vessel
development and recruiting CD4+ mononuclear cells through the expression of
interleukin-16. Circulation 2006, 113: 118–124
81 Ziegelhoeffer T,
Fernandez B, Kostin S, Heil M, Voswinckel R, Helisch A. Bone marrow-derived
cells do not incorporate into the adult growing vasculature. Circ Res 2004, 94:
230-238
82 Martens T, See FS, MD,
Sondermeijer H, Hefti M, Zannettino A, Gronthos S et al. Mesenchymal
lineage precursor cells induce vascular network formation in ischemic
myocardium. Nat Clin Pract Cardiovasc Med 2006, 3: 18–22
83 Sun L, Cui M, Wang Z,
Feng X, Mao J, Chen P. Mesenchymal stem cells modified with angiopoietin-1
improve remodeling in a rat model of acute myocardial infarction. Biochem
Biophys Res Commun 2007, 357: 779–784
84 Yang ZJ, Ma DC, Wang W,
Xu SL, Zhang YQ, Chen B. Experimental study of bone marrow-derived mesenchymal
stem cells combined with hepatocyte growth factor transplantation via
noninfarct-relative artery in acute myocardial infarction. Gene Ther 2006, 13:
1564–1568
85 Borgers M, Schaper J,
Schaper W. Acute vascular lesions in developing coronary collaterals. Virchows
Arch A Pathol Pathol Anat 1970, 351: 1–11
86 Pipp F, Boehm S, Cai WJ,
Adili F, Ziegler B, Karanovic G. Elevated fluid shear stress enhances
postocclusive collateral artery growth and gene expression in the pig hind
limb. Arterioscler Thromb Vasc Biol 2004, 24: 1664–1668
87 Rappolee DA, Mark D,
Banda MJ, Werb Z. Wound macrophages express TGF-alpha and other growth factors in
vivo: analysis by mRNA phenotyping. Science 1988, 241: 708–712
88 Hsieh MS, Ho HC, Chou
DT, Pan S, Liang YC, Hsieh TY. Expression of matrix metalloproteinase-9
(gelatinase B) in gouty arthritis and stimulation of MMP-9 by urate crystals in
macrophages. J Cell Biochem 2003, 89: 791–799
89 Mees B, Wagner S, Ninci
E, Tribulova S, Martin S, van Haperen R. Endothelial nitric oxide synthase
activity is essential for vasodilation during blood flow recovery but not for
arteriogenesis. Arterioscler Thromb Vasc Biol 2007, 27: 1926–1933
90 Lloyd PG, Yang HT,
Terjung RL. Arteriogenesis and angiogenesis in rat ischemic hindlimb: role of
nitric oxide. Am J Physiol Heart Circ Physiol 2001, 281: H2528–H2538
91 Yang HT, Ren J, Laughlin
MH, Terjung RL. Prior exercise training produces NO-dependent increases in
collateral blood flow after acute arterial occlusion. Am J Physiol Heart Circ
Physiol 2002, 282: H301–H310
92 Suchting S, Bicknell R,
Eichmann A. Neuronal clues to vascular guidance. Exp Cell Res 2006, 312: 668–675
93 Carmeliet P,
Tessier-Lavigne M. Common mechanisms of nerve and blood vessel wiring. Nature
2005, 436: 193–200
94 Eichmann A, Makinen T,
Alitalo K. Neural guidance molecules regulate vascular remodeling and vessel navigation.
Genes Dev 2005, 19: 1013–1021
95 Mukouyama YS, Shin D,
Britsch S, Taniguchi M, Anderson DJ. Sensory nerves determine the pattern of
arterial differentiation and blood vessel branching in the skin. Cell 2002,
109: 693–705
96 Villablanca AC, Murphy
CJ, Reid TW. Growth-promoting effects of substance P on endothelial cells in
vitro. Synergism with calcitonin gene-related peptide, insulin, and plasma
factors. Circ Res 1994, 75: 1113–1120
97 Kahler CM, Schratzberger
P, Wiedermann CJ. Response of vascular smooth muscle cells to the neuropeptide
secretoneurin. A functional role for migration and proliferation in vitro.
Arterioscler Thromb Vasc Biol 1997, 17: 2029–2035
98 Katayama I, Nishioka K.
Substance P augments fibrogenic cytokine-induced fibroblast proliferation:
possible involvement of neuropeptide in tissue fibrosis. J Dermatol Sci 1997,
15: 201–206
99 Dong YL, Reddy DM, Green
KE, Chauhan MS, Wang HQ, Nagamani M. Calcitonin gene-related peptide (CALCA) is
a proangiogenic growth factor in the human placental development. Biol Reprod
2007, 76: 892–899
100 Lambert N, Lescoulie PL,
Yassine-Diab B, Enault G, Mazieres B, De Preval C. Substance P enhances
cytokine-induced vascular cell adhesion molecule-1 (VCAM-1) expression on
cultured rheumatoid fibroblast-like synoviocytes. Clin Exp Immunol 1998, 113:
269–275
101 Yaraee R, Ebtekar M, Ahmadiani
A, Sabahi F. Effect of neuropeptides (SP and CGRP) on antigen presentation by
macrophages. Immunopharmacol Immunotoxicol 2005, 27: 395–404
102 Fernandez B, Buehler A,
Wolfram S, Kostin S, Espanion G, Franz WM. Transgenic myocardial overexpression
of fibroblast growth factor-1 increases coronary artery density and branching.
Circ Res 2000, 87: 207–213
103 Fischer-Colbrie R, Kirchmair
R, Kahler CM, Wiedermann CJ, Saria A. Secretoneurin: a new player in
angiogenesis and chemotaxis linking nerves, blood vessels and the immune
system. Curr Protein Pept Sci 2005, 6: 373–385
104 Yan S, Wang X, Chai H, Wang H,
Yao Q, Chen C. Secretoneurin increases monolayer permeability in human coronary
artery endothelial cells. Surgery 2006, 140: 243–251
105 Kirchmair R, Egger M, Walter
DH, Eisterer W, Niederwanger A, Woell E. Secretoneurin, an angiogenic
neuropeptide, induces postnatal vasculogenesis. Circulation 2004, 110: 1121–1127
106 Kirchmair R, Gander R, Egger
M, Hanley A, Silver M, Ritsch A. The neuropeptide secretoneurin acts as a
direct angiogenic cytokine in vitro and in vivo. Circulation
2004, 109: 777–783
107 Lee EW, Michalkiewicz M,
Kitlinska J, Kalezic I, Switalska H, Yoo P. Neuropeptide Y induces ischemic
angiogenesis and restores function of ischemic skeletal muscles. J Clin Invest
2003, 111: 1853–1862
108 Cai WJ, Koltai S, Kocsis E,
Scholz D, Kostin S, Luo X. Remodeling of the adventitia during coronary
arteriogenesis. Am J Physiol Heart Circ Physiol 2003, 284: H31–H40
109 Lloyd PG, Prior BM, Li H, Yang
HT, Terjung RL. VEGF receptor antagonism blocks arteriogenesis, but only
partially inhibits angiogenesis, in skeletal muscle of exercise-trained rats.
Am J Physiol Heart Circ Physiol 2005, 288: H759 H768
110 Miller DL, Ortega S, Bashayan
O, Basch R, Basilico C. Compensation by fibroblast growth factor 1 (FGF1) does
not account for the mild phenotypic defects observed in FGF2 null mice. Mol
Cell Biol 2000, 20: 2260–2268
111 Deindl E, Buschmann I, Hoefer
IE, Podzuweit T, Boengler K, Vogel S. Role of ischemia and of hypoxia-inducible
genes in arteriogenesis after femoral artery occlusion in the rabbit. Circ Res
2001, 89: 779–786
112 Smart N, Risebro CA, Melville
AA, Moses K, Schwartz RJ, Chien KR. Thymosin beta4 induces adult epicardial
progenitor mobilization and neovascularization. Nature 2007, 445: 177–182
113 Chiu JJ, Wung BS, Hsieh HJ,
Lo LW, Wang DL. Nitric oxide regulates shear stress-induced early growth
response-1. Expression via the extracellular signal-regulated kinase pathway in
endothelial cells. Circ Res 1999, 85: 238–246