Cardiovascular Research 65 (2005) 629 – 638
www.elsevier.com/locate/cardiores
Review
Role of neural guidance signals in blood vessel navigation
Monica Autiero, Frederik De Smet, Filip Claes, Peter Carmeliet*
The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology; University of Leuven, B-3000 Leuven, Belgium
Received 6 August 2004; received in revised form 14 September 2004; accepted 16 September 2004
Available online 20 October 2004
Time for primary review 20 days
Abstract
Despite the tremendous progress achieved in both vasculogenesis and angiogenesis in the last decade, little is still known about the
molecular mechanisms underlying the pathfinding of blood vessels during their formation. However, emerging evidence shows that different
axonal guidance cues, including members of the Slit and semaphorin families, are also involved in the blood vessel guidance, suggesting that
blood vessels and nerves share common mechanisms in choosing and following specific paths to reach their respective targets. These
promising findings open novel avenues not only in vascular biology but also in therapeutic angiogenesis. Indeed, the identification of new
molecules involved in the guidance of blood vessels may be helpful in designing angiogenic strategies, which would insure both the
formation of new blood vessels and their guidance into an organized and coordinated network.
D 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Keywords: Neural; Signals; Blood vessels
1. Introduction
In vertebrates, blood vessels form an extensive and
elaborate network, which is spatially organized to optimize
delivery of oxygen and nutrients to cells throughout the body
and removal of metabolites and waste products. During
embryonic development, endothelial precursors differentiate
and coalesce into tubes to form the central axial vessels (i.e.,
the dorsal aortae and the cardinal veins), a process called
dvasculogenesisT [1]. Subsequently, this primitive network
expands via sprouting, bridging and branching by intussusception (angiogenesis) and undergoes remodeling and
pruning of excess vessels to finally give rise to the complex
and hierarchical circuit, which is highly conserved among
vertebrate species [1,2]. In order to obtain a functional
network, mural cells [pericytes in medium-sized and smooth
muscle cells (SMC), in large vessels] are recruited around the
endothelial layer, stabilizing the endothelium by producing
an extracellular matrix (ECM; arteriogenesis) [2].
* Correspponding author. Tel.: +32 16 34 57 72; fax: +32 16 34 59 90.
E-mail address: [email protected] (P. Carmeliet).
Although a wealth of knowledge has been generated in
the past decade about the molecular mechanisms underlying
both vasculogenesis and angiogenesis, several critical
questions on how the vessels choose and follow specific
paths to reach their correct targets remain unanswered.
Understanding this process may have implications, not only
for vascular biology but also in the development of future
strategies for therapeutic angiogenesis. Indeed, for therapeutic angiogenesis to be successful in establishing a mature
and functional vascular network, two complementary
processes should be ensured: (i) the induction of new vessel
growth and (ii) the guidance of these vessels into a correctly
organized network.
Given the anatomical resemblance in the patterning of
nerves and blood vessels, much is likely to be learnt about
vessel patterning by studying the mechanisms of axon
guidance—a process, which has been more extensively
investigated in the past decade. Indeed, rapidly emerging
genetic studies in the mouse and zebrafish suggest that
blood vessels and nerves share common pathways for their
navigation towards their targets [3]. Due to space restrictions, the purpose of this review is not to provide an allencompassing overview, but to highlight the emerging links
0008-6363/$ - see front matter D 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.cardiores.2004.09.013
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M. Autiero et al. / Cardiovascular Research 65 (2005) 629–638
between the patterning of blood vessels and nerves, giving
particular attention to the netrins, slits, semaphorins and
vascular endothelial growth factor (VEGF). The role of
ephrins in vessel morphogenesis has been recently overviewed [4,5].
2. Blood vessels and nerves: different tasks, common
features
The vascular and nervous systems have several striking
anatomical similarities. They both consist of a highly
complex and precisely branched network, reaching the most
distant cells in the organism. The specialization of the
arterio-venous blood vessel system to transport oxygen and
remove carbon dioxide resembles the organization of the
nervous system to transmit, via afferent sensory and efferent
motor neurons, electrical impulses bidirectionally. Moreover,
both blood vessels and nerves consist of two cell types,
endothelial/mural cells, and neurons/glia, respectively.
In addition to sharing morphological features, both the
vascular and nervous systems develop by following similar
sequences of developmental events. As in the vascular
system, the first step in the nervous system development
involves the differentiation of progenitors into neurons with
the subsequent formation of central structures, such as the
neural tube and dorsal root ganglia. From these, the neurons
sprout axons to reach distal targets in a highly ordered and
stereotyped manner, thus establishing an intricately interconnected peripheral neural network [6–8]. Certain nerves
follow the path of blood vessels and are closely aligned with
branching vessels [9], raising the question whether the
molecular signals, governing branching of these two
systems, are related and interdependent. This hypothesis
has recently been supported by genetic mouse studies, for
instance, revealing that peripheral sensory nerves are
required both for the differentiation of small skin arteries
and the pattern of blood vessel branching [10]. In addition,
the neurotrophic factor artemin (ARTN), produced by SMC,
drives sympathetic nerves to follow vessels projecting
towards their targets [11].
Which are the molecular events taking place when nerves
and blood vessels navigate towards their respective targets?
At present, most of the currently available information is
deduced from studies on axon guidance, although insights
about vessel navigation are being increasingly generated.
When projecting along their trajectory, axons have to make
pathfinding decisions at the level of the so-called
dintermediate targetsT or dchoice pointsT [12]. The key
player in driving this pathfinding is the growth cone—a
highly motile structure located at the tip of the axon, which
explores the microenvironment, by extending finger-like
filopodia and veil-like lamellipodia, to detect and subsequently respond to a variety of guidance cues [13]. Both
diffusible and cell surface-associated molecules act as longor short-range pathfinding signals, respectively (see below)
[12]. As the growth cone extends in the microenvironment,
various molecular cues activate their respective receptors on
the growth cone surface and induce attractive and repulsive
signals. These signaling pathways are eventually integrated
and transmitted into changes of the cytoskeleton and growth
cone movement [14–17]. Assembly of the cytoskeleton
components results in growth cone advancement, its
disassembly leads to axon retraction, while asymmetric
signaling at one side of the growth cone induces turning and
a change in the direction of growth. Members of the Rho
family of small GTPases—primarily, Rac, Cdc42 and
Rho—play critical roles in this process by regulating the
dynamic changes of the actin cytoskeleton [18–21]. More
specifically, attractive guidance cues activate Cdc42 and
Rac while inhibiting RhoA, resulting in actin polymerization at the leading edge of the growth cone; conversely,
repulsive cues, through activation of RhoA and inhibition of
Rac and Cdc42, induce actinomyosin contraction. Relative
levels of the cyclic nucleotides cAMP and cGMP are also
known to regulate the growth cone response from repulsion
to attraction [22,23].
Similar mechanisms of pathfinding likely govern blood
vessel patterning—although they remain less well characterized. Recent findings characterized a class of specialized
endothelial cells at the leading edge of growing blood
vessels, i.e., the btip cellsQ, which are reminiscent of the
axonal growth cone. These tip cells act as sensors, transducers and motility devices, by extending their filopodia to
sample the microenvironment and by regulating the
extension of the capillary sprouts [24,25]. Given this
striking similarity between axon and vessel guidance, it
might be anticipated that both systems share common
guidance cues for their pathfinding. In the following
sections, we will focus on some of the families of such
guidance molecules. While some axon guidance signals
clearly also regulate vessel pathfinding, the evidence for
others is still circumstantial and being uncovered rapidly.
3. Guidance cues in axon pathfinding: do they have a
role in vessel guidance?
Considerable insight about the molecular basis of axon
pathfinding has been deduced from genetic studies in
invertebrates and the characterization of axon guidance in
vertebrate models, such as the projections of axons from
retinal ganglion cells and the commissural axons in the
spinal cord [26,27]. Overall, these studies have led to the
identification of different families of guidance cues, which
are highly conserved throughout the vertebrates: the Netrins,
Slits and Semaphorins will be discussed below.
3.1. Netrins
Three members of the netrin gene family have been
identified in mammals: netrin-1, netrin-3 and netrin4/h-
M. Autiero et al. / Cardiovascular Research 65 (2005) 629–638
netrin [28–32]. Netrins are secreted, diffusible proteins
related to laminin, which also bind to extracellular matrix
(ECM) components [33–35]. Their function has been
conserved throughout evolution, from worms to flies and
vertebrates. Genetic screens in C. elegans [36,37], loss-offunction studies in Drosophila [38,39] and mouse [40],
together with in vitro experiments with chicken neural
explants [28,33], revealed that netrins, secreted by midline
cells, attract commissural axons towards the ventral midline of the central nervous system. However, these
molecules have also been demonstrated to repel some
axons, such as the trochlear motor axons in vertebrates
[41–44]. Interestingly, this dual activity to attract or repel
axons depends on the receptor type to which the netrins
bind. Two families of netrin transmembrane receptors have
been identified in vertebrates: (i) the Deleted in Colorectal
Cancer (DCC) family, consisting of DCC and neogenin
[45] which are homologues of the C. elegans UNC-40
[36,46] and the Drosophila Frazzled protein [47]; and (ii)
the UNC5 family, consisting of UNC5H-1, -2, -3 and -4
[48–51], which share homology with the C. elegans UNC5 [52]. Recently, the A2b receptor, a member of the
adenosine receptor family, has been identified as a novel
netrin-1 receptor in mammals [53], but its function remains
controversial and largely unknown [53,54]. Biochemical
and genetic studies in different species demonstrated that
axon attraction is mediated by the DCC/UNC40 receptors
[45,46,55], while repulsion requires signaling by the UNC5
family receptors, acting either alone or in combination with
DCC family receptors [36,43,56]. UNC5 is capable of
mediating short-range repulsion by netrin, while both
UNC5 and DCC are required to mediate long-range
repulsion by netrin, when its concentrations are low
[43,56]. This cooperation between UNC5 and DCC
involves a direct interaction of their cytoplasmic domains,
as demonstrated by ectopic expression of rat UNC5H2 in
Xenopus commissural neurons [56]. Thus, netrins are key
guidance molecules for different axons, acting over a short
range (close to the surface of the cells producing them) or
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over a long range (up to a few millimeters distant from
their source; reviewed in Ref. [57]).
Although very little is known about a possible role of
netrins in the morphogenesis of organs outside the nervous
system, their wide developmental expression pattern suggests that these molecules may have such a role [30,31,58].
Indeed, netrin-1/neogenin regulate mammary gland morphogenesis by assuring close apposition of cap cells and
preluminal cells at the leading edge of the terminal end buds
[59]. In the context of vessel patterning, it is interesting to
note that, in addition to its expression in the neural tube,
netrin-1b is also expressed in the zebrafish hypochord [60],
a transient structure ventral to the notochord in the
amphibian and fish embryo, which is known to be involved
in the patterning of the dorsal aorta [61,62]. Our recent
studies (in collaboration with A. Eichmann and M. TessierLavigne) indeed indicate that loss or knockdown of
UNC5H2 or netrin in mice and zebrafish cause abnormal
vessel guidance and excessive vessel branching, indicating
that netrin-1 and UNC5H2 provide critical repulsive
guidance cues for navigating vessels [156] (Table 1).
3.2. Slits
Another intriguing class of guidance cues is the Slit
family, which includes large, secreted proteins, highly
conserved from C. elegans to vertebrates [63–66]. In
mammals, three members, i.e., Slit-1, -2 and -3, are all
expressed in the nervous system, with Slit-2 and -3 being
also expressed elsewhere [65,67–69]. Slit proteins typically
have multiple binding domains, including four leucine-rich
repeats (LRRs), that are critical for biological functions,
nine (seven in Drosophila) EGF-like repeats, which are
thought to control Slit diffusion, and a C-terminal cystein
knot [70–73]. Although Slit proteins were identified
originally in Drosophila almost 20 years ago [74], their
role has been elucidated only recently. Indeed, in vitro and
genetic studies in Drosophila and mouse demonstrated that
midline-derived Slits act as chemo-repellents, by preventing
Table 1
Overview of the vascular phenotypes (excluding defects involving only the heart) observed during development of mice or zebrafish morphants in which either
a guidance molecule or its receptor has been knocked down
Targeted gene
Vascular phenotype in mouse
Vascular phenotype in zebrafish
Netrin-1
Not reported
UNC5H2
Abnormal vessel patterning [156]
Robo-4
Sema3A
Not reported
Abnormal development of the anterior cardinal vein and of the
intersomitic vessels [120]
Intersomitic blood vessel defects and pharyngeal arch patterning defects [122]
Impairment of neural vascularization, abnormal and highly
variable patterns of great vessels and vascular defects in the yolk sac [124]
Severe reduction of small lymphatic and capillaries [126]
Lack of blood vessel formation in the yolk sac, avascular
regions in the head and the trunk and lack of capillary plexus [127]
Abnormal vessel patterning and excessive branching
[156]
Abnormal vessel patterning and excessive branching
[156]
Intersomitic blood vessel defects [92]
Delayed development of the dorsal aorta [119]
PlexinD1
Npn-1
Npn-2
Npn-1/Npn-2
Intersegmental vessel patterning defects [123]
Impaired circulation in the intersomitic vessels [125]
Not reported
Not reported
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M. Autiero et al. / Cardiovascular Research 65 (2005) 629–638
ipsilateral axons from crossing the midline and commissural
axons from recrossing it [63,64,75,76]. This repulsion is
mediated by Slit interaction with receptors of the Roundabout (Robo) family, which have been identified in
organisms ranging from Drosophila, C. elegans to vertebrates [75,77–80]. Members of this family are single-pass
transmembrane proteins with an extracellular region containing five immunoglobulin (Ig) domains and three
fibronectin type III repeats [77,80]. In mammals, four Robo
receptors, Robo-1, -2, -3 and -4, have been identified, with
Robo-4 (also referred to as Magic Roundabout) being
structurally divergent from the other proteins because it
lacks two Ig domains and one fibronectin repeat [77,81–83].
Studies in Drosophila clarified the mechanisms by which
the commissural axons are first attracted by netrins towards
the midline and, once they have crossed it, are prevented to
recross the midline by becoming responsive to the repulsive
activity of the Slit proteins. Prior to reaching the midline,
expression of Robo on axonal growth cones is repressed by
Commissureless (Comm) [78], which secures that Robo is
retained in intracellular compartments [84]. Upon crossing
the midline, Comm loses this suppressive activity, so that
Robo becomes exposed onto the cell surface, thereby
making the growth cone responsive to Slit. Activation of
Robo also silences the attractive effect of netrin, via a direct
interaction of the cytoplasmic domain of Robo to that of the
netrin receptor DCC (as shown by a study on embryonic
Xenopus spinal axons [85]), thereby facilitating expulsion of
the commissural axons away from the midline. Various lines
of evidence suggest that a similar system is also operational
in mammals. Similar to Comm in Drosophila, Robo-3 in
mammals prevents precrossing spinal commissural axons
from responding to floor plate Slit repellents, thereby
allowing commissural axons to become attracted to the
midline [86]. Upon crossing the midline, commissural axons
become responsive to Slit [87], explaining why these axons
either do not leave or recross the midline irregularly in triple
Slit knockout mice [76].
In addition to the well-characterized role of Slit proteins
in axon guidance, a growing body of evidence shows that
they are involved in the migration of different cell types,
including neuronal cells [88], chemotactic leukocytes [89],
neural crest cells [90] and myoblasts [91]. Notably, Robo-4
is specifically expressed on endothelial cells in both the
embryo and adult, and significantly upregulated in tumor
vessels and in mice with vascular sprouting and patterning
defects (i.e., mice lacking the activin receptor-like kinase 1
gene) [83,92]. In vitro, Slit-2 inhibits the migration of Robo4-expressing endothelial cells, consistent with a repulsive
activity [92]. Another study suggested, however, that Slit-2,
via Robo-1, attracts endothelial cells via Robo-1 activation
[93]. Slit-2 is expressed in various solid tumors, whereas
Robo-1 is upregulated in tumor vessels and neutralization of
Robo-1 inhibits tumor growth in vivo [93]. Furthermore,
knockdown of Robo-4 expression induces abnormal patterning of intersomitic vessels in zebrafish [94]. Thus, Slit-
2/Robo-4 provides repulsive cues for endothelial cells in
vitro, whereas Slit-2/Robo-1 signals chemoattract endothelial cells in tumors in vivo (Fig. 1). These puzzling findings
raise the question whether vascular Slit may act as an
attractive or a repulsive cue, depending on the receptor to
which it binds.
3.3. Semaphorins
Semaphorins belong to a large family of phylogenetically conserved secreted and membrane-associated proteins, characterized by the presence of a highly conserved
~500 amino acid extracellular semaphorin domain (dsemaT)
at their amino termini, which mediates binding to its
receptor (reviewed in Refs. [95,96]). To date, more than 20
different semaphorins have been identified, which are
divided into eight classes on the basis of sequence
similarities and structural features (Semaphorin Nomenclature Committee, 1999). The first two classes consist of
invertebrate semaphorins, while classes 3 to 7 include
vertebrate semaphorins and class V comprises the viral
sempahorins. In vitro as well as genetic studies in flies and
mice have shown that semaphorins primarily act as
repulsive cues on a wide number of neurons (e.g., dorsal
root ganglion neurons in the peripheral nervous system and
hippocampal neurons in the central nervous system), by
diverting axons from inappropriate regions, or driving them
through a repulsive corridor [97–102]. Interestingly,
semaphorins are also capable of chemoattracting certain
Fig. 1. Attractive and repulsive cues mediating the guidance of the
endothelial tip cell growth cone. VEGF and Slit-2 act as attractant cues, via
Flk1 and Robo-1, respectively, while Sema3A and Slit-2 act as repulsive
cues, via Npn1/PlexinD1 and Robo-4, respectively. It should be mentioned
that the involvement of Slit-2/Robo-4 axis in repulsion is based on in vitro
experiments.
M. Autiero et al. / Cardiovascular Research 65 (2005) 629–638
axonal populations, such as mitral cell axons of the
olfactory bulb during development [103–106]. Cytosolic
levels of cGMP seem to play a critical role in converting
the response of neurons to semaphorins from repulsion to
attraction [22]. Overall, these data indicate that semaphorins may be bifunctional guidance cues, endowed with
attractive or repulsive activities, similar to the netrin family
members. This dual activity depends on the restricted
distributions of these proteins, on the receptor complexes
to which semaphorins bind (see below) and on the crosstalk between semaphorin receptors and other pathways
[107]. Two major family receptors have been implicated in
mediating the action of semaphorins: plexins and neuropilins. Specifically, invertebrate semaphorins, membraneassociated semaphorins in vertebrates and viral semaphorins directly interact with plexins [108–110]. In contrast,
vertebrate class 3 secreted semaphorins utilize receptor
complexes consisting of neuropilin, serving as the ligandbinding component, and plexin, functioning as the signaltransducing component [111–114]. To date, two neuropilins, Npn-1 and Npn-2, and nine plexins (Plex-A1, -2, -3,
-4; Plex-B1, -2, -3; Plex-C1, -D1) have been identified in
mammals (reviewed in Ref. [115]). Neuropilins are also
receptors for particular isoforms of the vascular endothelial
growth factor (VEGF; see below). Additional transmembrane proteins, including the Drosophila off-track (Otk)
and the hepatocyte growth factor (HGF)-receptor Met have
been recently shown to be either semaphorins receptors or
components of receptor complexes [96,116,117]. Thus, the
wide range of possible combinations of the different
members of the semaphorin receptor complex may be in
part responsible of the specificity of responses of different
neurons to semaphorins.
Like netrins and Slits, semaphorins are also expressed
outside the central nervous system and their role is not only
restricted to neural development. Indeed, they are also
involved in the migration and/or morphogenesis of epithelial cells [116,118], as well as in the migration of both
leukocytes [119] and tumor cells [120]. Interestingly,
emerging evidence also suggests a role of Semaphorin 4D
(Sema4D) and Semaphorin 3A (Sema3A) in vascular
development. Indeed, Sema4D induces endothelial cell
migration and tubulogenesis in vitro and stimulates blood
vessel formation in vivo [121]. Zebrafish Sema3a1 regulates
migration of the angioblasts, which give rise to the dorsal
aorta [122], whereas endothelial-derived class 3 semaphorins control endothelial cell migration in chick embryos, via
autocrine inhibition of integrin-mediated adhesion of
endothelial cells to the extracellular matrix [123]. In
addition, Sema3A seems to mediate the topographical
congruence of nerves and blood vessels during the quail
forelimb development [124]. Recent studies in mouse and
zebrafish highlighted a critical role of Sema3 proteins in
vessel guidance [125,126] (Table 1). In these studies,
disruption of the signaling, triggered by the interaction of
Sema3 proteins with endothelial PlexinD1, likely in com-
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plex with Npns, caused aberrant patterning of intersomitic
vessels in zebrafish and mice, thus suggesting that
semaphorins line repulsive corridors, through which the
intersomitic blood vessels traverse (Fig. 1). Although
genetic loss of Npn-1 and/or Npn-2 causes significant
vascular defects in mice and fish [127–130], it remains
unclear to what extent these defects are caused by abnormal
signaling of VEGF and/or semaphorins. Indeed, vascular
development, but not axonal pathfinding, was normal in
mice expressing a Npn-1 variant, unable to bind to Sema3A
[131]. Future work will be required to resolve the complex
molecular mechanism of semaphorins and neuropilins in
vascular development.
4. VEGF: a guidance cue for vessels and nerves?
Numerous studies established that VEGF is a key player
of angiogenesis [132,133]. In this review, we will focus our
attention on how VEGF regulates vessel patterning and
neural development. In mammals, different isoforms are
generated by alternative splicing from a single VEGF gene
(reviewed in Ref. [134]). Specifically, six isoforms
(VEGF121, VEGF145, VEGF165, VEGF183, VEGF189 and
VEGF206) have been identified in humans, with VEGF165
being the predominant form [135]. Mouse and rat isoforms
are one amino acid shorter than their human counterparts.
While VEGF121 is a soluble protein and does not bind
heparin, the longer isoforms show increasing binding to
heparan sulfate-containing proteoglycans of the extracellular
matrix, from which they can be released by proteolytic
enzymes [135]. These isoforms also exhibit a distinct tissuespecific expression pattern [136] and have different biological properties (see below). All VEGF isoforms bind the
tyrosine-kinase receptors VEGFR-1 [also known as fms-like
tyrosine kinase (Flt1)] and VEGFR-2 [also known as fetal
liver kinase (Flk1)] [134], but only VEGF165 binds both
Npn-1 and -2, while VEGF145 binds Npn-2 [137,138].
VEGF stimulates endothelial cell proliferation and
survival, primarily through Flk1 signaling [139–141].
Interestingly, Flk1 signaling is enhanced by Npn-1, which
thus acts as a coreceptor for VEGF165 [142]. Genetic
studies in mice revealed that the various VEGF isoforms
have distinct roles in vessel guidance. Indeed, vascular
development was normal in mice exclusively expressing
VEGF164, indicating that this isoform is required and
sufficient for vessel guidance [143]. In contrast, in
VEGF120/120 mice, which express only the VEGF120
isoform, endothelial cells become integrated in enlarging
vessels at the expense of vessel branching [143,144].
VEGF 188/188 mice, expressing the matrix-associated
VEGF188 isoform, exhibit opposite defects, characterized
by excess branching at the expense of vessel lumen
enlargement [143,144]. Overall, these results indicate that
the different VEGF isoforms cooperate to form a gradient
extending from the target tissue to the tip cell of the
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M. Autiero et al. / Cardiovascular Research 65 (2005) 629–638
growing vessel, thus providing long-range and shortrange guidance cues for correct vessel patterning
(Fig. 1).
In recent years, increasing attention has been given to
the possible role of VEGF in the nervous system [145].
Both VEGF and Flk1 are expressed by neurons [146]. In
vitro experiments demonstrated that VEGF/Flk1-signaling
promotes axonal outgrowth [146,147], neuronal survival
[146,148,149] and neuroprotection against glutamate cytotoxicity [150,151]. Moreover, VEGF, expressed by ependymal cells at sites of neurogenesis, enhances selfrenewal, fate and proliferation of neuronal stem cells both
in vitro and in vivo [152,153]. VEGF also acts as a
chemoattractant for undifferentiated neural progenitors
[154]. By competing with Sema3A for binding to Npn1, VEGF165 prevents the collapse of dorsal root ganglia
axons [155]. In addition, Flk1 is present on the growth
cones of regenerating axons [146]. Nonetheless, it remains
to be established whether VEGF is a relevant axon
guidance cue.
5. Concluding remarks
Several lines of evidence are starting to shed light on
the molecular mechanisms underlying blood vessel pathfinding during development, while highlighting that blood
vessels and nerves share common guidance cues during
their navigation to reach their final target. Although
additional studies are required to better elucidate this link
between blood vessel and axon pathfinding mechanisms,
the initial findings provide new perspectives in the design
of angiogenic therapeutic strategies not only able to
promote the formation of new vessels but also to guide
them into a coordinated network.
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