Advances in the Cellular and Molecular Biology of Angiogenesis
New insights into the plasticity of the endothelial
phenotype
Lindsay S. Cooley1 and Dylan R. Edwards
School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, Norfolk NR4 7TJ, U.K.
Abstract
The mammalian vascular system consists of two distinct, but closely related, networks: the blood vasculature
(itself divided into arterial and venous networks) and the lymphatic vasculature. EC (endothelial cell) lineage
specification has been proposed to be determined during embryonic development, after which the ECs are
committed to their fate. However, increasing evidence suggests that ECs retain various degrees of plasticity,
and have the ability to express characteristics of alternative cell lineages. Therapeutic control of endothelial
plasticity will allow greater understanding of the genesis and treatment of several vascular diseases.
Introduction to the blood and lymphatic
vascular systems
The mammalian vascular system consists of two related, but
functionally distinct and specialized, networks: the blood
and lymphatic vascular systems. The primary roles of the
blood vascular system are to deliver oxygen and nutrients
to the organs and tissues, and the removal of metabolic
waste [1]. It is divided into two anatomically distinct, but
closely interconnected, networks of arteries and veins. The
lymphatic vasculature plays a complementary role to that of
the blood vascular system by collecting fluid from the tissues
and returning it to the blood supply via the thoracic duct.
As such, it is essential for tissue fluid homoeostasis, and also
plays vital roles in the immune response via the transport
of antigen-presenting cells to the lymph nodes, as well as in
absorption of lipids from the intestinal tract [2].
The blood and lymphatic vascular systems share many
structural features, and have a common origin. However,
these two circulatory systems are functionally distinct, and
separation must be maintained for each to function correctly,
suggesting that they must also be subject to different
regulatory mechanisms. As such, BECs (blood vascular
endothelial cells) and LECs (lymphatic endothelial cells)
have been recognized as functionally distinct cell types with
characteristic profiles of gene expression [3–6].
Blood vascular development
The blood vasculature develops in the early embryo via
vasculogenesis, in which endothelial precursor cells form
a primitive vascular plexus [7]. Subsequent remodelling of
this plexus occurs via angiogenesis [8]. As mature ECs
(endothelial cells) develop, and as venous and arterial EC
types are specified, blood vessels (veins and arteries) are
formed.
Specification of arterial and venous identity is complex.
Molecular differences between arterial and venous ECs
are genetically programmed, and are evident before the
formation of the first vessels or embryonic heart. Molecular
markers of arterial and venous fate include ephrinB2 and
its receptor EphB2 (which mediate ‘repulsive’ signalling,
allowing arterio–venous separation) and Hedgehog, VEGF
(vascular endothelial growth factor)-A and neuropilin [9].
The key regulator of arterial fate is the Notch signalling
pathway (itself induced in response to VEGF signalling) and,
in particular, its target transcription factors Hey1 and Hey2.
Notch signalling promotes arterial cell fate differentiation,
and suppresses venous fate choices [10–15]. Similarly,
the COUP-TFII (chicken ovalbumin upstream promotertranscription factor 2) transcription factor is expressed in
venous, but not arterial, ECs, and has been shown to be
a positive regulator of venous cell fate, repressing Notch
signalling [16]. However, during early development, lineage
specification has a degree of plasticity, with grafted vessels
of one type able to take on characteristics of the other in
response to environmental cues such as blood flow and cell–
cell interactions [17,18]. It is also possible for cells to switch
lineage entirely during development, since the mammalian
coronary artery is formed by redifferentiation of mature
venous cells of the sinus venosus into arterial cells [19].
Surprisingly, a degree of plasticity is maintained in the adult,
since veins grafts from aged mice or adult human lose their
venous markers when grafted into arteries, although they fail
to show induction of aortic markers [20].
Key words: artery, blood system, endothelial cell, lymphatic system, plasticity, vein.
Abbreviations used: BEC, blood vascular endothelial cell; COUP-TFII, chicken ovalbumin upstream
promoter-transcription factor 2; EC, endothelial cell; ECM, extracellular matrix; EMT, endothelial–
mesenchymal transition; FOXC2, forkhead box C2; IL, interleukin; LEC, lymphatic endothelial cell;
Prox1, prospero homeobox protein 1; VEGF, vascular endothelial growth factor; VEGFR3, VEGF
receptor 3.
1 To whom correspondence should be addressed (email [email protected]).
Biochem. Soc. Trans. (2011) 39, 1639–1643; doi:10.1042/BST20110723
Origin of the lymphatic vasculature
Although the lymphatic vasculature was originally described
hundreds of years ago, it has historically been relatively
understudied, in large part due to the lack of specific
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markers available to differentiate the lymphatic from the
blood vasculature. However, in the last decade, a number
of genes have been identified as differentially expressed
in lymphatic compared with blood vasculature. Markers
commonly used to identify lymphatic ECs include the
homeobox transcription factor Prox1 (prospero homeobox
protein 1), considered to be the ‘master regulator’ of the
lymphatic phenotype [21], the hyaluronan receptor LYVE-1
[22], the receptor tyrosine kinase VEGFR3 (VEGF receptor
3) [23], the mucin-type glycoprotein receptor podoplanin [24]
and integrin α9 [25].
In the developing mammalian embryo, the lymphatic
vasculature develops after the blood vasculature, and
lymphatic vessels are closely associated to blood vessels
in vivo. The widely accepted model of mammalian lymphatic
development proposes that the lymphatic system originates
from a subset of ECs in the embryonic cardinal vein, with
lymphatic identity occurring via the stepwise expression
of lymphatic genes [26]. Specification of the lymphatic fate is
controlled by three key transcription factors: COUP-TFII,
Sox18 and Prox1. Sox18 can be thought of as a ‘competency’
factor which interacts with COUP-TFII to specify target
cells in which expression of Prox1, the master regulator of the
lymphatic lineage, is induced [27,28]. At this point, the cells
are committed to the lymphatic lineage [21]. They migrate
away from the cardinal vein and go on to give rise to the
entire lymphatic lineage. During this process, other lymphatic
regulatory genes are expressed, and blood vascular regulatory
genes are down-regulated [29].
New insights from classic in vitro
angiogenesis models
Although the process described above is the only known
example of true venous–lymphatic transdifferentiation,
recent evidence suggests that venous–lymphatic lineage
specification is also more plastic than previously believed.
Traditional in vitro models of angiogenesis use primary
ECs, which have the ability to form capillary-like tubular structures when suspended within three-dimensional
matrices of various ECM (extracellular matrix) components.
By looking at the molecular profile of cells forming capillaries,
and comparing it with cells cultured as standard monolayers,
our laboratory has observed that BECs take on a ‘lymphaticlike’ gene expression profile [30]. This is characterized by the
co-ordinated up-regulation of a set of ‘lymphatic’ genes with
down-regulation of a set of blood vascular marker genes.
Surprisingly, this process occurred using a variety of EC
types, including arterial as well as venous cells, and when
ECs were cultured in various matrices of type I collagen,
fibrin and MatrigelTM . These findings suggest that many, if
not all, EC types may be able to switch to a lymphatictype phenotype. Interestingly, although the angiogenesis
assays model aspects of endothelial tubulogenesis (migration,
alignment, attachment, lumen formation etc.), the capillary
formation process was not required for induction of
C The
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Authors Journal compilation the ‘LEC’ phenotype, since it occurred when the tube
formation process was blocked using a broad-spectrum
matrix metalloproteinase inhibitor (BB-94). Rather, the ECM
environment was crucial for this process, since removal
of the ECs from the ECM was able to completely reverse
the process and ECs regained their typical BEC expression
profile.
A key structural difference between blood and lymphatic
vessels in vivo is that blood vessels are encircled by mural
cells (smooth muscle cells or pericytes), whereas lymphatic
vessels show sparse or no mural cell coverage [31]. We
showed that co-culturing BECs with perivascular cells could
partially abrogate induction of the lymphatic-like phenotype,
with siRNA (small interfering RNA)-mediated inhibition of
expression of the Prox1 transcription factor having a similar
effect. These results showed that cell–cell contacts are also
important for the regulation of phenotype, and suggest that
they may directly or indirectly regulate expression of key
genes such as Prox1.
Plasticity of BECs and LECs
Our earlier study [30] represents (to our knowledge) the first
example of BECs ‘spontaneously’ showing altered expression
of lineage marker genes due to an altered extracellular
environment; however, there are other reports in the literature
of BECs having been induced to express LEC markers [32].
It is well documented that reprogramming of BECs to the
LEC lineage can be ‘forced’ via the ectopic expression of the
master regulator Prox1 [33,34]. It is also known that infection
of BECs with Kaposi’s sarcoma-associated herpesvirus (a
malignancy associated with chronic inflammation) has a
similar effect [35,36]. Inflammatory cytokines have also been
reported to induce lymphatic marker gene expression. Prox1
and podoplanin induction was reported in HUVECs (human
umbilical vein endothelial cells) treated with IL (interleukin)3 [37], and, in vivo, blood vessels expressing LYVE-1
and podoplanin protein have been detected in chronically,
but not acutely, inflamed skin [38]. In angiosarcomas,
intratumoral capillaries have been reported to express a mixed
blood/lymphatic phenotype [39], and re-expression of the
lymphatic receptor VEGFR3 has been reported in tumour
vasculature [40]. The postnatal expression of LEC genes in
BECs in these contexts has been described as pathogenic
lymphangiogenesis [32].
Control of BEC/LEC switching
What could regulate the adoption of a ‘lymphatic phenotype’
by BECs? The examples given above suggest possible
mechanisms.
Inflammation
It is notable that, in many of the reported cases of
adoption of expression of lymphatic regulatory genes by
BECs, the cells were exposed to inflammatory cytokines.
Since growth factors such as VEGF-A, VEGF-C, HGF
Advances in the Cellular and Molecular Biology of Angiogenesis
(hepatocyte growth factor) and various ILs are known to
induce lymphangiogenesis (including proliferation of LECs)
during inflammatory processes [41], it is possible that these
factors may play a role in induction of key LEC regulatory
genes. It would be interesting to assess the potential of other
growth factors/cytokines to induce reprogramming of BECs
to LECs both in vitro and in vivo.
Figure 1 EC specification determined by the balance of key
lineage regulators
See the text for further details.
Cell–cell interactions
There is evidence of key roles played by mural cells in the
maintenance of EC lineage identity. For example, during
quail-chick grafting experiments, arterial ECs retained their
phenotype longer when arterial smooth muscle cells were
included in the graft, indicating that interactions between the
two cell types influenced lineage identity [17]. Interestingly,
our study showed that co-culturing BECs with mural
cells induced the same pattern of marker expression as
inhibition of the lymphatic regulator Prox1, suggesting
that cell–cell interactions themselves may be regulated by
downstream signalling from key lineage regulatory genes,
or vice versa [30]. This is supported by the finding that, in
mice in which Prox1 was conditionally inactivated, lymphatic
vessels became abnormally invested with mural cells [42]. A
mechanism for this is unclear, but could involve regulation
of factors involved in lymphatic endothelial–mural cell
interactions. A possible candidate is the FOXC2 (forkhead
box C2) transcription factor, since inactivation of the Foxc2
gene in mice results in abnormal recruitment of pericytes
to lymphatic vessels due to up-regulation of PDGF-BB
(platelet-derived growth factor-BB) [43].
Cell–ECM interactions
The role of the ECM environment is clearly complex and,
in our earlier study [30], was central to the induction
of the lymphatic phenotype. The role of the extracellular
environment is known to be crucial for maintenance of EC
lineage maintenance, since BEC and LEC transcriptional
programmes are lost during standard monolayer EC culture
in vitro [44]. Mechanotransductive effects of the ECM are
likely to regulate the EC phenotype. It is well established
that gene expression and cell differentiation are regulated by
matrix conditions such as stiffness [45,46], and in our study
[30], different patterns of marker gene expression could be
induced by the same matrix components when cells were
seeded on top, rather than embedded within them. At this
stage, the mechanisms by which the matrix regulates gene
expression and cell differentiation have not been elucidated.
However, as mediators of cell–ECM interactions, integrins
are a key target for future investigation. Although evidence
is building for the roles of various integrins in both blood
vascular and lymphatic biology [47], further research is
required to elucidate their exact roles in BEC and LEC
lineage specification. We have identified a number of integrins
whose expression is altered during BEC tubulogenesis. These
include up-regulation of integrins α9, α10 and β4, and
down-regulation of α2, α6 and α5; further investigation
will determine whether these or other potential candidate
integrins directly regulate EC lineage specification.
Balance of lineage regulator genes
As discussed above, arterial–venous identity is regulated by a
negative-feedback loop between Notch signalling in arteries
and COUP-TFII signalling in veins. Lymphatic ECs express
all three cell fate regulators, i.e. Notch [48], COUP-TFII
[16] and Prox1 [21], with Notch signalling counteracting
Prox1 and COUP-TFII [49], and Prox1 expressed in BECs
able to counteract COUP-TFII signalling [50]. This suggests
the concept that endothelial lineage identity is finely regulated
by the balance of these key regulatory pathways [49],
illustrated in Figure 1. Thus the switch from a BEC to a LEC
phenotype could occur via altered expression or activity of
key regulators. For example, down-regulation of the venous
regulator COUP-TFII could remove negative regulation of
Prox1, leading to its increased expression or activity, in turn
leading EC to being able to express lymphatic marker genes.
Although an exact mechanism remains to be elucidated, it
is clear that ‘outside-in’ signalling as a result of the factors
described above (cell–cell or cell–ECM interactions, cytokine
stimulation etc.) could lead to an altered balance of key
regulatory genes.
Perspectives
EC lineage specification has been proposed to be determined
during embryonic development, after which ECs are
irreversibly fixed and committed to their fate. However,
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mounting evidence suggests that flexibility in lineage
specification exists in all EC types, both early in development
and in the adult. The studies discussed in the present article
suggest the possibility that many, if not all, ECs retain the
capacity to express features of alternative EC lineages, with
phenotype regulated by environmental as well as genetic cues.
Thus the concept of EC as fixed non-interconvertible cell
types may need to be re-examined. A practical corollary
of this is that researchers must be careful to verify their
experimental methods and models of EC culture to ensure
their expected EC lineage characteristics are maintained,
since our study suggests that traditional EC monoculture
tubulogenesis assays model aspects of lymphangiogenesis
rather than angiogenesis.
Understanding EC plasticity and regulation of lineage
specification by the extracellular environment will have
implications for our knowledge of the genesis and treatment
of disease. It is possible that, under normal conditions, steadystate levels of the relevant lineage regulators are maintained,
but that in pathological conditions such as inflammation
and tumorigenesis, an altered extracellular environment could
lead to an altered balance of regulators and reprogramming of
ECs. An increased understanding of this process could lead
to its therapeutic manipulation in a variety of contexts. For
example, an increased production of LEC-type cells could
ameliorate hereditary or secondary lymphoedema caused by
lymphatic insufficiency, whereas reduction of LECs could
improve treatment of inflammatory conditions or inhibit
tumour lymphangiogenesis. Adult venous grafts used in
coronary bypass surgery have a lower success rate compared
with arterial grafts [51,52], potentially because they do
not acquire a full arterial phenotype [20], and improved
manipulation of arterial–venous plasticity is likely to improve
their clinical outcome.
Although an in-depth discussion is outside of the scope
of the present review, it is also important to mention
other types of endothelial plasticity which may also
be therapeutically significant. Endothelial progenitor and
various other stem-like cells are extremely plastic, and can be
induced to form mature BECs and LECs, as well as a variety
of other cell types including smooth muscle cells [53,54].
This makes them a promising therapeutic avenue for various
vascular diseases. Mature ECs can also be induced to take on
stem-cell-like properties via EMT (endothelial–mesenchymal
transition), and these cells can then be redifferentiated to
various other cell types, including osteoblasts, chondrocytes
and adipocytes [55] which may be of therapeutic benefit.
However, this process can have negative health effects.
Tumour ECs can also undergo EMT, and can take on features
of adult stem cells, with various effects including conversion
into invasive and migratory cancer-associated fibroblasts
[56,57]. Interestingly, tumour cells themselves can acquire an
endothelial-type phenotype, expressing endothelial markers
and gaining the ability to form vessel-like structures in a
process known as vasculogenic mimicry [58,59]. Therapeutic
control of EC and EC-like tumour cell plasticity is likely to
be of benefit in future cancer treatments.
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Authors Journal compilation Funding
This study was supported by BigC, the Suzie Wright Fund, and the
Biotechnology and Biological Sciences Research Council.
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Received 31 August 2011
doi:10.1042/BST20110723
C The
C 2011 Biochemical Society
Authors Journal compilation 1643