The role of pericytes in angiogenesis
DOMENICO RIBATTI*,1, BEATRICE NICO1 and ENRICO CRIVELLATO2
1Department of Human Anatomy and Histology, University of Bari Medical School, Bari, and 2Department of
Medical and Morphological Research, Anatomy Section, University of Udine Medical School, Udine, Italy
ABSTRACT Pericytes are branched cells embedded within the basement membrane of capillaries
and post-capillary venules. They provide an incomplete investment to endothelial cells, thus
reinforcing vascular structure and regulating microvascular blood flow. Pericytes exert an
important role on endothelial cell proliferation, migration and stabilization. Endothelial cells, in
turn, stimulate expansion and activation of the pericyte precursor cell population. The balance
between the number of endothelial cells and pericytes is highly controlled by a series of signaling
pathway mechanisms operating in an autocrine and/or paracrine manner. In this review, we will
first examine the molecular aspects of the pericyte activating factors secreted by endothelial cells,
such as platelet derived growth factor B (PDGF-B), vascular endothelial growth factor (VEGF),
transforming growth factor beta (TGF- ) and angiopoietins (Angs), as well as signaling pathways
involving Notch and ephrins. We will then consider the complex and multivarious contribution of
pericytes to the different aspects of angiogenesis with particular emphasis on the potential role
of these cells as targets in tumor therapy.
KEY WORDS: angiogenesis, antiangiogenesis, pericyte, tumor growth
Pericytes are advential cells located within the basement
membrane of capillary and post-capillary venules. Because of
their multiple cytoplasmic processes, distinctive cytoskeletal ele-
ments and envelopment of endothelial cells, pericytes are gener-
ally considered to be cells that stabilize the vessel wall, controlling
endothelial cell proliferation and thereby the growth of new
capillaries. In addition, they are believed to participate in the
regulation of microvascular blood flow via a contractile mecha-
Charles Rouget was the first to describe branched, non-
pigmented cells on the capillary wall of the hyaloid of the frog and
regarded them as contractile elements (Rouget, 1873, 1874,
1879), but he was unable to stain these cells and concluded that
they were muscle cells. Staining of Rouget cells was successfully
carried out by Mayer in 1902, using methylene blue. Mayer (1902)
suggested that pericytes merge into smooth muscle cells of the
tunica media or arteries.
Vimtrup (1922), studying capillaries in tails of different young
living larvae, noted that “the contraction of capillaries begins at
one of these cells (pericytes), spreading in both directions, at first
slowly, later significantly faster”. He confined his studies to areas
where the afferent arterioles and the efferent venules were clearly
Int. J. Dev. Biol. 55: 261-268 (2011)
THE INTERNATIONAL JOURNAL OF
*Address correspondence to: Domenico Ribatti. Department of Human Anatomy and Histology. University of Bari Medical School. Piazza G. Cesare, 11
Policlinico, E-70124 Bari, Italy. Fax: +39.080.5478310. e-mail: email@example.com
Accepted: 23 September 2010. Final author corrected PDF published online: 15 June 2011.
ISSN: Online 1696-3547, Print 0214-6282
© 2011 UBC Press
Printed in Spain
Abbreviations used in this paper: Ang, angiopoietin; Eph, ephrin; NG, nerve/
glial antigen; PDGF, platelet-derived growth factor; TGF, transforming
growth factor; VEGF, vascular endothelial growth factor.
visible, thus allowing unequivocal identification of the capillary
segment in-between. He termed the observed contractile popula-
tion as “Rouget cells”.
The term pericytes was later coined by Zimmermann in 1923.
He demonstrated that pericytes were: a) present around capillar-
ies in a wide range of species including fish, amphibians, reptiles,
birds and mammals; b) continuous with smooth muscle cells of
arteries and veins; c) highly branched with distinctive cytoplasmic
processes within each capillary bed. Moreover, Zimmermann
held that contraction of these cells controlled capillary permeabil-
ity and distinguished three subgroups of pericytes, depending on
the type of vessel pericytes are located at, but already considered
the existence of a continuum with countless forms of differentia-
Pericytes are commonly identified by molecular markers, such
as alpha smooth muscle actin, non-muscle myosin, tropomyosin,
262 D. Ribatti et al.
desmin, nestin, platelet derived growth factor receptor- (PDGFR-
), aminopeptidase A, aminopeptidase N (CD 13), sulfatide or
nerve/glial antigen-2 (NG2) proteoglycan (Morikawa et al., 2002)
(Fig. 1). Pericytes on normal capillaries typically express desmin,
but not alpha smooth muscle actin, whereas smooth muscle cells
on arterioles and pericytes on venules are immunoreactive for
both (Nehls and Drenckhahn, 1993; Morikawa et al., 2002). Other
reports have suggested that alpha smooth muscle actin may be
considered a general marker for pericytes (Hellstrom et al., 1999;
Ohlsoon et al., 1999).
The balance between endothelial cells and pericytes
The balance between the number of endothelial cells and
pericytes seems to be highly controlled. Potential regulators
include soluble factors acting in an autocrine and/or paracrine
manner, mechanical forces secondary to blood flow and blood
pressure, as well as homotypic and heterotypic cell contacts.
Severals molecules are involved in the control and modulation
of the interactions occurring between pericytes and endothelial
cell, such as PDGF-B, transforming growth factor beta (TGF-),
vascular endothelial growth factor (VEGF), angiopoietins (Angs),
signaling pathways involving Notch and ephrins (Hughes, 2008;
von Tell et al., 2006).
Endothelial production of PDGF-B is required for peri-
Endothelial cells secrete PDGF-B and pericytes express
PDGFR- (Betsholtz, 2004), suggesting a paracrine mode of
interaction between these two cell types (Fig. 2). PDGF-B pro-
motes pericyte precursor cell proliferation and migration and mice
deficient for PDGF-B or PDGFR- die during embryonic develop-
ment with widespread microvascular defects, consisting in vessel
dilatation and microaneurysms. In most tissues of these animals
pericyte association with vessels is drastically reduced (Betsholtz,
2004). Endothelial cells of the sprouting capillaries in the PDGF-
B deficient mice were unable to attract PDGFRB--positive pro-
genitors of pericytes. Failure to recruit pericytes during develop-
ment leads to vascular instability and regression (Benjamin et al.,
1998; Leveen et al., 1994; Lindbloom et al., 2003).
Greenberg et al. (2008) demonstrated that under conditions of
PDGF-mediated angiogenesis, VEGF abolished pericyte cover-
age of vascular sprouts, leading to vessel destabilization. VEGF-
mediated activation of VEGFR-2 suppressed PDGFR- signal-
ing, through the induction of a VEGFR-2/ PDGFR- complex (Fig.
TGF- 1 contributes to the differentiation of precursor
cells into pericytes
When mesenchymal cells are co-cultured with endothelial cells
or treated with TGF-1, they express smooth muscle cell markers,
indicating differentiation of precursor cells into pericytes or smooth
muscle cells (Darland and D’Amore, 2001). Mice deficient for
endoglin, a TGF-1 co-receptor, display reduced association with
smooth muscle cells and pericytes (Li et al., 1999). TGF-1
inhibits endothelial cell proliferation and migration, and mice
deficient for TGF-1 signaling components show dilated and
irregularly shaped microvessels (Lebrin et al., 2005). Overall,
these data indicate that TGF-1 appears to be instrumental for the
de novo induction of pericytes by regulating differentiation of
VEGF induces proliferation and migration of pericytes
and pericyte-derived VEGF promotes endothelial cell
VEGF directly induces proliferation and migration of pericytes
in hypoxic conditions (Yamagishi et al., 1999) and also indirectly
stimulate pericyte recruitment via endothelial cell production of
nitric oxide (NO). In turn, NO promotes mural precursor cell
migration in vitro and pericyte recruitment to tumor vessels in
vivo (Kashiwagi et al., 2005). Treatment with VEGF inhibitors
causes pericytes to become closely associated with surviving
tumor vessels in Lewis lung carcinomas, RIP-Tag2 tumors
(Inai et al., 2004) and other tumor models (Tong et al., 2004;
Willett et al., 2004).
Darland et al. (2003) demonstrated that pericytes co-
cultured with endothelial cells produce VEGF that may act in
a juxtacrine/paracrine manner as a survival and/or stabilizing
factor for endothelial cells. Moreover, they observed VEGF
gene expression in developing retinal vasculature in pericytes
contacting newly formed microvessels.
Fig. 1. Cytoplasmic markers (above) and membrane determinants (be-
low) expressed by pericytes.
Pericyte-derived Ang-1 promotes endothelial cell
survival and Ang-2 acts as a destabilizing factor and
the balance of Ang-1 and Ang-2 signaling regulates
The Angs family consists of Ang-1, -2, and the orthologous
Ang-3 in mouse and Ang-4 in human. All Angs bind the
endothelial-specific receptor tyrosine kinase Tie-2 (also known
as TEK) and play a critical role in endothelial sprouting, vessel
wall remodeling and mural cell recruitment (Thurston, 2003).
Pericytes in angiogenesis 263
Ang-1 is produced by pericytes and smooth muscle cells,
activates endothelial Tie-2, maximizes interactions between en-
dothelial cells and pericytes and is expressed behind the leading
edge of angiogenic vessels, a position consistent with vessel
maturation (Sundberg et al., 2002). Mice deficient for either Ang-
1 or Tie-2 die during embryonic development with vascular
defects similar to those observed for PDGF-B deficient mice
(Jones et al., 2001). Ultrastructural analysis suggests that Tie-2-
knock out blood vessels lack mural cells (Patan, 1998). In PDGF-
B deficient mice, recombinant Ang-1 restored the vascular struc-
ture and permeability in the growing retinal vasculature (Uemura
et al., 2002). Moreover, Ang-1 also counteracts VEGF-induced
endothelial leakiness (Thurston et al., 1999).
Ang-2 is expressed by endothelial cells located at the leading
edge of proliferating vessels (Maisonpierre et al., 1997) and acts
as a destabilizing factor which is restricted to endothelial cells in
areas of vascular remodeling and binds Tie-2 without inducing
signal transduction (Maisonpierre et al., 1997).
Expression of both Ang-2 and Tie-2 in pericytes has been also
reported (Wakui et al., 2006; Cai et al., 2008). VEGF increases
production of Ang-2, and overexpression of Ang-2, which binds to
Tie-2 in competition with Ang-1, by endothelial cells results in
dissociation of pericytes from vessels (Zhang et al., 2003), re-
duces pericyte coverage and destabilizes vessels within the
tumor even in the presence of VEGF stimulation (Cao et al.,
2007). Moreover, transgenic mice overexpressing Ang-2 in the
retina develop dense vascular networks with reduced pericyte
coverage (Feng et al., 2007). De Palma et al. (2005) demon-
strated that monocytes expressing Tie-2 (TEMs) are a distinct
haemopoietic lineage of proangiogenic cells and distin-
guished a subpopulation of tumor stroma-derived mesen-
chymal progenitor cells representing a primary source of
NG2 and Notch-3 mediate pericyte-endothelial
Immature pericytes express the NG2 proteoglycan dur-
ing early stages of angiogenesis and soluble NG2 pro-
motes endothelial cell motility and angiogenesis forming a
complex with galectin-3 and 31 integrin on the cell
surface (Fukushi et al., 2004). Both blocking by antibodies
as well as knocking out of the gene encoding NG2 abro-
gated vascular growth (Ozerdem and Stallcup, 2004).
Virgintino et al. (2007) have shown that microvessels of
the fetal human telencephalon are characterized by a
continuous layer of NG2-positive pericytes, which tightly
invest endothelial cells in the earliest stages of vessel
Notch signaling is a highly conserved pathway, initially
discovered in Drosophila development (Baron et al., 2002).
There are four Notch receptors (Notch 1-4) and five
ligands (Jagged-1, and –2, Delta 1, -3, -4) (Iso et al., 2003).
All the receptors and ligands are expressed in at least one
vascular compartment, e.g. arteries, veins, capillaries,
muscle cells or pericytes.
Notch signaling is required for remodeling the primary
vascular plexus into the hierarchy of mature vascular beds
and maintaining arterial fate (Alva and Iruela-Arispe, 2004).
The Notch-3 receptor is highly expressed in pericytes and disrup-
tion of Notch-3 signaling in Notch-3 -/- mutant mice results in
enlarged vessels due to the lack of pericytes (Wang et al., 2007).
Patients suffering from CADASIL (Cerebral Autosomal Dominant
Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)
syndrome, pathology associated with mutations of Notch-3, present
vessels lacking pericytes (Louvi et al., 2006). In dental pulp,
perivascular cells mainly express Notch-3 (Lovschall et al., 2007)
and in the retina pericytes express also Notch-3 (Claxton and
Fruttiger, 2004). More recently, Liu et al. (2009) showed that
knockdown by small interfering RNA revealed that Notch-3 sig-
naling is necessary for endothelial-dependent mural cell differen-
tiation, and Notch-3 contributes to the pro-angiogenic capability of
mural cells co-cultured with endothelial cells.
Fig. 2. Schematic drawing that illustrates the paracrine interactions occur-
ring between pericyte precursor cells and endothelial cells in PDGF-medi-
ated angiogenesis. Endothelial cells secrete PDGF-B, that causes pericyte
precursor cell proliferation and migration through activation of PDGFR- receptors.
Pericytes surround and cover early endothelial tubes. By contrast, endothelial cells
in vascular sprouts release VEGF, which in turn mediates suppression of PDGFR-
signaling through the induction of VEGFR-2/PDGFR- complexes. This pathway
abrogates pericyte coverage of endothelial sprouts leading to vascular instability
Ephrins and Eph receptors
The discovery that members of the ephrins (Eph) family are
differentially expressed in arteries and veins from very early
stages of development has been one of the first indications that
artery-vein identity is intrinsically programmed. Eph-B2 is ex-
pressed in arterial endothelial cells. The principal receptor for
Eph-B2, Eph-B4, displays a reciprocal expression pattern in
embryonic veins (Bratley-Siders and Chen, 2004). Mutations of
the Eph-B2 and of Eph-B4 both lead to early embryonic lethality
(Wang et al., 1998; Adams et al., 1999; Gerety et al., 1999; 2002).
Remodeling of the primary vascular plexus into arteries and veins
was arrested in both mutants, suggesting important roles for Eph-
B2/Eph-B4 interactions on arterial and venous endothelial cells,
264 D. Ribatti et al.
Ephrin-B2 is a critical regulator of mural cell migration, spread-
ing and adhesion during vessel wall assembly (Foo et al., 2006).
More recently, Salvucci et al. (2009) reported that Eph-B is a
critical mediator of postnatal pericyte to endothelial cell assembly
into vascular tubes. Furthermore, inhibition of Eph-B activity
prevents assembly of pericytes and endothelial cells.
The role of pericytes in angiogenesis
During the initial phase of angiogenesis, activated pericytes in
parent vessels bulge, shorten their processes and increase their
volume, an intense cell proliferation occurs, pericytes project into
the perivascular spaces, their basement membrane is disrupted
and fragmented and appear detached from the vessel wall (Diaz-
Flores et al., 1992). Although initially endothelial cell sprouts may
form without pericyte involvement, pericytes are among the first
cells to invade newly vascularized tissues and locate at the
growing front of the endothelial sprouts by determining the loca-
tion of sprout formation and by guiding newly formed vessels
(Nehls et al., 1992). Individual pericytes can be found at the tips
of angiogenic sprouts in the corpus luteum, where pericytes are
the first vascular cells to invade the granulose fold of the ruptured
follicle, and in tumors (Amselgruber et al., 1999; Gerhardt and
Betsholtz, 2003; Morikawa et al., 2002).
It has long believed that endothelial tube formation is
followed by investment of pericytes, which use endothe-
lial cell sprouts as migration clues. Accordingly, pericytes
are recruited by differentiation from surrounding mesen-
chymal precursors or by migration from the mural wall of
the adjacent vessel (Gerhardt and Betsholtz, 2003). In
this way, pericytes suppress endothelial growth (Orlidge
and D’Amore, 1987) and migration (Sato and Rifkin,
1989). There is a striking coincidence of pericyte invest-
ment and microvessel stabilization (von Tell et al., 2006;
Bergers and Song 2005) and pericyte investment has
also been directly implicated in conferring capillary resis-
tance to regression in vivo (Benjamin et al., 1998).
Clinical evidence for a stabilizing function of pericyte was
offered by the finding that the development of
microaneurysms of retinal capillaries, as a symptom of
diabetic retinopathy, was correlated with an initial loss of
intramural pericytes (Kuwabara and Cogan, 1963).
In 1990, Blood and Zetter wrote that: “Formation of a
basement membrane and investment of capillaries with
pericytes are generally associated with the end of the
proliferative stage and the beginning of the mature or
quiescent stage of capillary function”. More recently,
Stratman et al. (2009) have demonstrated that endothe-
lial cell-pericyte interactions regulate increased expres-
sion of basement membrane protein genes and proteins,
such as fibronectin and laminin, as well as integrins that
recognize the remodeled matrices to control this process
and these changes occur specifically in endothelial cell-
pericyte co-cultures and not in endothelial cell only cul-
Alternatively, pericytes can invade tissues in the ab-
sence of endothelial cells and can form tubes enabling
the subsequent penetration of endothelial cells (Ozerdem
and Stallcup, 2003). Rajantie et al. (2004) showed that bone
marrow-derived hematopoietic progenitors cells CD11b+ and
CD45+ expressing the pericyte marker NG2 were located in close
proximity to blood vessels in a subcutaneous B16-F10 melanoma
model. Bone marrow-derived PDGFR-+/Sca-1+ progenitor
pericytes have been demonstrated in mouse model of pancreatic
islet tumorigenesis, which were able to differentiate into mature
pericytes expressing the markers NG2 and alpha smooth actin
(Song et al., 2005). Virgintino et al. (2007) demonstrated in the
human fetal telencephalon that growing microvessels are formed
by a pericyte-driven angiogenic process in which endothelial cells
are preceded and guided by migrating pericytes.
Overall, these data suggest the existence of a mutual interplay
between endothelial cells and pericytes in the direction of the
angiogenic process, assigning to the pericytes a putative morpho-
Pericytes as targets in tumor therapy
In pathological conditions in which angiogenic activity is en-
hanced, such as tumors, pericytes are located near blood vessels
at the growing front of tumors, where angiogenesis is most active
and show morphological abnormalities (Schlingemann et al.,
1990; Wesseling et al., 1995; Morikawa et al., 2002). Moreover,
Fig. 3. Signaling pathways operating in endothelial cell/pericyte paracrine
cross-talk. Pericytes are involved in endothelial cell stimulation and guidance as
well as endothelial stabilization and maturation. Vessel sprouts (right) cause
destabilization of pericyte investment through Ang-2/Tie-2 signaling. Pericytes
provide guidance for endothelial movement and tube formation through secretion
of VEGF and soluble NG-2. Spreading endothelial cells, in turn, stimulate pericyte
precursor cell proliferation and migration by releasing VEGF and NO. Vessel
stabilization (left) occurs by pericyte investment and close interaction with endot-
helial cells. Mature endothelial cells secrete PDGF-B, which promotes proliferation
and migration of pericyte precursor cells through activation of PDGFR- receptors
expressed on the surface of pericyte progenitors. This mechanism leads to pericyte
coverage of early endothelial tubes. Vessel maturation further develops through
Ang-1- and Notch-mediated signaling. Pericyte stabilize and reinforce the endothe-
lial tube contributing to secretion of basal membrane.
Pericytes in angiogenesis 265
pericyte deficiency could be partly responsible for vessel abnor-
malities in tumor blood vessels (Gerhardt and Semb, 2008) and
partial dissociation of pericytes (Hobbs et al., 1998; Hashizume et
al., 2000) contribute to increased tumor vascular permeability.
VEGF inhibition eliminates tumor vessels without removing
pericytes (Morikawa et al., 2002). Antiangiogenic treatment di-
rected against endothelial cells using VEGF inhibitors induces the
regression of tumor vessels and decreases tumor size (Baluk et
al., 2005), leading to vessel normalization, characterized by
increased pericyte coverage, tumor perfusion and chemothera-
peutic sensitivity (Jain, 2005). Moreover, removal of VEGF inhi-
bition causes tumor re-growth due to the fact that pericytes
provide a scaffold for the rapidly re-growing of tumor vessels
(Mancuso et al., 2006).
Pericytes have been indicated as putative targets in the phar-
macological therapy of tumors by using the synergistic effect of
anti-endothelial and anti-pericytic molecules. Removal of pericyte
coverage leads to exposed tumor vessels, which may explain the
enhanced effect of combining inhibitors that target both tumor
vessels and pericytes. Bergers et al. (2003) showed that com-
bined treatment or pre-treatment with anti-PDGF-B/PDGFBR-
reducing pericyte coverage increases the success of anti-VEGF
treatment in the mouse RIP1-TAG2 model.
However, extensive regression of endothelial cells was not
observed in tumors after inhibition of PDGFR- signaling
(Abramsson et al., 2003). STI571 (Gleevec, Imatinib), which
targets PDGFRs and other receptor tyrosine kinases, did not
reduce vascular density when given alone but did augment the
effects of VEGF inhibitors (Bergers et al., 2003). After treatment
of RIP1-TAG-2 tumors and Lewis lung carcinomas with AG-
013737 or VEGF-Trap, surviving pericytes may become more
tightly associated with endothelial cells or have no apparent
association with tumor vessels (Inai et al., 2004). Treatment of
RIP1-TAG2 tumors with anti-PDGFR- antibody for three weeks
reduces pericytes, increases endothelial cell apoptosis but does
not seem to reduce tumor vascular density (Song et al., 2005).
Similarly, the receptor tyrosine kinase inhibitor SU6668, which
also affects PDGFR- signaling, detaches and reduces pericytes
in RIP1-TAG2 and xenotransplanted tumors, thereby restricting
tumor growth (Reinmuth et al., 2001; Shaheen et al., 2001).
Sennino et al. (2007) demonstrated that treatment with a novel
selective PDGF-B blockade DNA aptamer AX102 that blocks the
action of PDGF-B led to progressive reduction of pericytes in
Lewis lung carcinomas. More recently, Murphy et al. (2010)
generated a series of selective type II inhibitors of PDGFR- and
B-RAF targets for pericyte recruitment and endothelial survival,
respectively and they demonstrated that dual inhibition of both
PDGFR- and B-RAF exerted synergistic antiangiogenic activity
in both zebrafish and murine models of angiogenesis.
Several other important studies with the aim to target pericytes
have been conducted in experimental tumor models (Pietras and
Hanahan, 2005; Maciag et al., 2008; Lu et al., 2010), and even in
a human trial in advanced renal cell carcinoma (Haisnworth et al.,
We have recently demonstrated that combined targeting of
pericytes and endothelial tumor cells with a combination of a
peptide ligand of aminopeptidase A (APA), disovered by phage
display technology for deliver of liposomal doxorubicin (DXR) to
perivascular tumor cells, and aminopeptidase N (APN)-targeted
liposomal DXR enhances anti-tumor efficacy of liposomal chemo-
therapy in human neuroblastoma-bearing mice (Loi et al., 2010).
Pericytes are critical cells in vascular biology. They intervene
at different levels of blood vessel formation, being involved in
endothelial cell stimulation and guidance as well as endothelial
stabilization and maturation. Signaling pathways operating in
endothelial cell-pericyte cross-talk are currently being investi-
gated and will provide crucial information on the paracrine mo-
lecular mechanisms controlling capillary formation (Fig. 3). This
point is of critical interest in the physiopathological and clinical
approach to degenerative vasculopathies as well as tumor angio-
genesis. Finding drugs that allow manipulation of pericyte/endot-
helial cell interactions will provide physicians with a potent tool
capable of controlling and blocking vascular proliferation and
permeability. Increase of pericyte recruitment to stabilize new
vessels will potentially ameliorate vascular disorders, such as
diabetic retinopathy. In addition, a stable capillary microvascula-
ture may represent an important prerequisite for preventing tumor
cell dissemination. The future use of molecules interfering with
the endothelial cell/pericyte unit will be also of interest in tissue
engineering as well as the development of multi-tissue organs.
Further studies are needed to highlight further aspects of pericyte
molecular biology and physiology.
Supported in part by MIUR (PRIN 2007), Rome, AIRC, Milan, and
Fondazione Cassa di Risparmio di Puglia, Bari, Italy.
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