Review
Pharmacological approaches
to improve endothelial
repair mechanisms
Expert Rev. Cardiovasc. Ther. 6(8), xxx–xxx (2008)
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Author for correspondence
Cardiovascular Center, University
Hospital Zurich, Raemistrassse
100, 8091 Zurich, Switzerland
Tel.: +41 442 559 595
Fax: +41 442 554 251
[email protected]
ho
†
Endothelial injury is thought to play a pivotal role in the development and progression of vascular
diseases such as atherosclerosis, hypertension or restenosis, and their complications, including
myocardial infarction or stroke. Accumulating evidence suggests that bone marrow-derived
endothelial progenitor cells (EPCs) promote endothelial repair and contribute to ischemia-induced
neovascularization. Coronary artery disease and its risk factors, such as diabetes,
hypercholesterolemia, hypertension and smoking, are associated with a reduced number and
impaired functional activity of circulating EPCs. Moreover, initial data suggest that reduced EPC
levels are associated with endothelial dysfunction and an increased risk of cardiovascular events,
compatible with the concept that impaired EPC-mediated vascular repair promotes progression
of vascular disease. In this review we summarize recent data on the effects of pharmacological
agents on mobilization and functional activity of EPCs. In particular, several experimental and
clinical studies have suggested that statins, angiotensin-converting enzyme inhibitors, angiotensin
II type 1 receptor blockers, PPAR-γ agonists and erythropoietin increase the number and
functional activity of EPCs. The underlying mechanisms remain largely to be defined; however,
they likely include activation of the PI3-kinase/Akt pathway and endothelial nitric oxide synthase,
as well as inhibition of NAD(P)H oxidase activity of progenitor cells.
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Christian Besler,
Carola Doerries,
Giovanna Giannotti,
Thomas F Lüscher
and Ulf Landmesser†
Keywords: endothelial regeneration • endothelium • EPC • nitric oxide • oxidant stress
Role of the endothelium & endothelial
function in cardiovascular disease
A
ut
During the last 20 years, numerous experimental and clinical studies have demonstrated
that the endothelium plays a crucial role in the
regulation of vascular tone and structure [1–3] .
Under physiological conditions, the endothelial
monolayer does not only maintain the balance
between vasodilation and vasoconstriction,
but also inhibits leukocyte and platelet adhesion, and platelet aggregation as well as exerting anticoagulant and profibrinolytic effects
(F igure 1) [1,4] .
Endothelial dysfunction has been identified
as a common link between the known cardiovascular risk factors, such as diabetes, hypercholesterolemia, smoking and hypertension and
is characterized by a proinflammatory and prothrombotic phenotype of the endothelium [5,6] .
Early on, atherosclerosis was considered to be
an inflammatory–fibroproliferative response to
various forms of insult to the endothelium [7] .
Today it has become clear that atherosclerosis
www.expert-reviews.com
10.1586/14779072.6.8.xxx
is an inflammatory disease [8,9] and the degree
of inflammation has prognostic significance [10] .
Activation of endothelial cells therefore plays
a crucial role in recruitment and adhesion of
leukocytes, whose infiltration into the arterial
wall is a critical step in development of atherosclerotic lesions [11,12] .
Hence, disruption of endothelial integrity,
both functionally and structurally, either in
response to major cardiovascular risk factors or
by direct mechanical injury (i.e., after percutaneous coronary intervention), induces a variety
of proinflammatory and proliferative responses
in the arterial wall, contributing to initiation
and progression of atherosclerotic plaque formation, vascular remodeling and development of
restenosis [13–15] .
Therefore, there is increasing interest in
the effect of pharmacological approaches, to
maintain structural and functional integrity
of the endothelium, in part by promoting
endothelial repair and preventing endothelial
cell apoptosis.
© 2008 Expert Reviews Ltd
ISSN 1477-9072
1
Review
Besler, Doerries, Giannotti, Lüscher & Landmesser
A
B
Neovascularization
Circulating EPCs
Functions of
endothelial
progenitor cells
Anticoagulant and
profibrinolytic effects
Anti-inflammatory
effects
Endothelial cell functions
Antihypertrophic
effects on vascular
smooth muscle cells
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Endothelium-dependent
vasodilation
Direct
incorporation
ro
Paracrine
effects
of
Antithrombotic
effects
Reendothelialization
Expert Rev. Cardiovasc. Ther. © Future Science Group Ltd (2008)
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Figure 1. Vasoprotective functions of the healthy endothelium and potential role of EPCs in vascular repair processes. (A)
The healthy endothelium not only mediates endothelium-dependent vasodilation, but also exerts anti-inflammatory, antithrombotic and
anticoagulant effects and suppresses vascular smooth muscle cell hypertrophy. (B) EPCs have been shown to promote endothelial repair
and augment ischemia-induced neovascularization, either by paracrine effects on adjacent mature endothelial cells or direct
incorporation into the endothelial monolayer or a combination of both. EPC: Endothelial progenitor cell.
EPCs & cardiovascular events
Endothelial repair has long been thought to depend exclusively
on the proliferation and migration of local adjacent endothelial
cells [16] . In 1997, Asahara et al. described for the first time a
population of putative endothelial progenitor cells (EPCs) in
human peripheral blood [17] . In this study, selected circulating
CD34 + cells were shown to differentiate into mature endothelial
cells ex vivo and to contribute to neoangiogenesis in hindlimb
ischemia (Figure 1) . Since then, numerous studies have suggested
that blood-derived EPCs promote endothelial repair after vascular injury [18–20] , contribute to ischemia-induced myocardial
and peripheral neovascularization [21] and improve endothelial
function [22] . Moreover, a recent study by Foteinos et al. has
suggested that bone-marrow derived endothelial progenitor cells
contribute to endothelial repair in lesion-prone areas of experimental atherosclerosis [23] .
Importantly, several cardiovascular risk factors reduce circulating numbers and impair functional activity of circulating EPCs,
suggesting a loss of endogenous endothelial repair capacity in
patients at high risk for cardiovascular events (Figure 2) [24,25] .
Altered EPC levels were demonstrated in several clinical studies, for patients with stable coronary artery disease [26] , heart
failure [27] , peripheral vascular disease [28] and cerebrovascular
disease [29] .
In a study of 519 patients with coronary disease, reduced circulating EPC levels were associated with an adverse cardiovascular
outcome in a follow-up period of 12 months; that is to say, lower
numbers of CD34 +/kinase insert domain receptor (KDR)+ double-positive blood-derived mononuclear cells were associated with
a higher risk of cardiovascular events [30] . Moreover, in a study of
120 individuals by Schmidt-Lucke et al. including patients with
stable coronary disease, acute coronary syndrome and control
subjects, reduced numbers of peripheral blood CD34 +/KDR+
progenitor cells independently predicted cardiovascular events
over a median follow-up period of 10 months [31] . Of note, in this
study, the number of circulating EPCs remained an independent
predictor of poor prognosis after adjustment for common cardiovascular risk factors, suggesting that impaired EPC-mediated
vascular repair may be relevant for progression of cardiovascular
disease [31] .
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Endothelial repair mediated by circulating EPCs
2
EPC subpopulations
A large number of bone marrow transplantation studies suggest that EPCs can be derived from the bone marrow [32] . More
recently it has become clear that tissue-resident stem cells are an
additional source of circulating progenitor cells [33] . However,
there is currently no precise agreement on the exact definition
Expert Rev. Cardiovasc. Ther. 6(8), (2008)
Pharmacological approaches to improve endothelial repair mechanisms
PPARγ agonists
Benidipine
Statins
Review
cells; however, the amount of cells obtained
after FACS was rather low and this may be
a limiting factor that should be considered
in the interpretation of these data.
Culture analysis
PPARγ
Culture analysis of EPCs is mostly performed
by using blood-derived mononuclear cells.
With respect to characterization of EPCs in
culture, it has become clear that there are
PPARγ
Proliferation
+
several cell populations in peripheral blood
+
differentiation
Akt
mononuclear cells, which may promote
migration
–
–
endothelial repair or neovascularization
Apoptosis
in different ways [32] . In particular, recent
data have suggested that at least two EPC
+
subpopulations can be grown from periph–
NAD(P)H
oxidase
eral blood mononuclear cells, namely early
eNOS
EPCs and late-outgrowth endothelial cells
(OECs), promoting angiogenesis in different ways [36] . Early EPCs, which have been
NO
suggested to arise primarily from a CD14 +
O2subpopulation of peripheral blood mononuclear cells [37] , failed to form vascular netReendothelialization capacity
works
and to incorporate in endothelial-like
Expert Rev. Cardiovasc. Ther. © Future Science Group Ltd (2008)
structures in a newly developed angiogenesis
assay, but contributed to tubulogenesis in a
Figure 3. Postulated mechanisms mediating the effects of pharmacological
agents on EPCs. Statins, EPO and benidipine have been suggested to exert their effects
paracrine fashion. OECs, likely arising from
on EPC functional activity, at least in part, via the phosphoinositide 3-kinase (PI3K)/Akt
CD14- peripheral blood mononuclear cells
pathway. Furthermore, endothelial nitric oxide synthase has been implicated for the
[37] , augmented tubulogenesis by directly
effects of statins, PPAR-γ agonist and EPO on EPCs. PPAR-γ agonists may exert their
incorporating into newly formed vascular
effect on EPCs, at least part, via antioxidant NAD(P)H oxiase-inhibiting effects. EPC:
networks, but failed to stimulate tubulogenEndothelial progenitor cells; EPO: Erythropoietin.
esis in a paracrine fashion when separated
of endothelial progenitor cells. The examination of EPCs is at from mature endothelial cells in a transwell technique [36] .
Of note, it has been observed that hematopoietic progenitor cells
present largely performed by two ways: by FACS analysis of total
blood cells or circulating mononuclear cells; and by analysis of can differentiate towards both endothelial and vascular smooth
muscle-like cells [38,39] . Circulating progenitor cell-derived vascultured blood-derived mononuclear cells.
cular smooth muscle-like cells have been suggested to contribute
to vascular remodeling after wire-induced neointima formation
FACS analysis
As described previously, hematopoietic progenitor/stem cell mark- or restenosis [38,39] . Therefore, the differentiation of circulating
ers, in particular CD34 and/or CD133, are used in combination progenitor cells towards either endothelial or vascular smooth
with endothelial cell markers (particular KDR, also known as muscle like cells may also play an important role for the overall
VEGFR-2) to quantify circulating EPCs in peripheral blood [34] vascular effects of circulating progenitor cells.
Thus, additional studies are necessary, not only to define the
and for these measurements, the initial data suggest a relation to
cardiovascular prognosis, as described previously. The rationale for precise origin, phenotype and subtypes of circulating EPCs, but
using these markers is, at least in part, based on the observation that also to characterize the functional role and differentiation potenboth isolated CD34+ and isolated KDR+ cells from peripheral blood tial of circulating progenitor cell-derived vascular smooth musclemay differentiate in vitro towards endothelial cells and contribute to like cells in more detail.
ischemia-induced neovascularization [17] . However, this approach
has not been supported by a precise phenotypic and functional Effect of pharmacological therapies in clinical use on
characterization of these double-positive cells. Recently, Case et al. endothelial repair mechanisms
have assessed the capacity of CD34 +/CD133 +/KDR+ cells (isolated Several pharmacological agents have been shown to impact on the
by magnetic-activated cell sorting and FACS) to form endothelial- number and function of EPCs in experimental and small-scale
like cell colonies [35] . In this study, the authors could not detect prospective clinical studies. Besides clinically used pharmacologiendothelial colony formation from CD34 +/CD133 +/KDR+ cells cal agents, a number of cytokines, growth factors (e.g., VEGF
and questioned their capacity to differentiate towards endothelial and IGF) and hormones (e.g., estrogen) have been studied for
PI3K
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EPO
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3
Review
Besler, Doerries, Giannotti, Lüscher & Landmesser
their impact on EPC-mediated endothelial repair in experimental
studies. In this review, however, we focus on recent data about the
effects of pharmacological agents in clinical use for treatment of
cardiovascular risk factors that affect mobilization and functional
activity of EPCs (Table 1) .
Statins & EPC homing
Statins
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The mechanisms by which statins increase EPC numbers and
functional activity are not completely understood. Of note, the
statin-induced increase in EPC numbers and myocardial neovascularization in the infarct border zone was dependent on endo
thelial nitric oxide synthase (eNOS), since we did not observe
these responses in eNOS -/- deficient mice [44] . A reduced bone
marrow matrix metalloproteinase (MMP)-9 activity has been
suggested to contribute to impaired stem-cell and progenitor cell
mobilization in eNOS-deficient mice [45] ; however, recent studies did not observe an effect of statin therapy on bone marrow
MMP-9 activity despite a significant mobilization of EPCs [46] .
Therefore, the effects of statins on eNOS appear to be critical
for EPC mobilization; however, the exact mechanisms whereby
statins mobilize EPCs remain to be explored.
Whereas several studies have shown that short-term statin treatment increases the number of circulating EPCs as detected by
CD34 +/KDR+ cells or by culture assays of early EPCs, a recent
retrospective study has suggested that long-term statin therapy
(>8 weeks) may be associated with reduced EPC numbers, potentially as a result of increased EPC homing [47] . This observation,
however, needs further confirmation.
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Statins & EPC mobilization
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Several studies have suggested that the number and functional
activity of circulating EPCs, as characterized by both, FACS and
culture analysis, are increased by statins in mice and in patients
with coronary disease or heart failure [19,20,40–43] . Moreover, in
experimental studies, statin therapy accelerated re-endothelialization after balloon injury, that was associated with increased mobilization and incorporation of bone marrow–derived EPCs at the site
of injury and a subsequently decreased neointima formation [19,20]
Importantly, studies of bone marrow transplantation using Tie2/
lacZ mice [19] , or studies using retrovirally transfected bone marrow cells [20] , revealed that bone marrow-derived EPCs are directly
recruited to endothelium-denudated areas of the arterial wall.
Statin treatment of human early EPCs was found to upregulate
the expression of endothelial integrin subunits α5 and β1, composing the fibronectin receptor, and αv and β5, which was associated
with increased adhesiveness of EPCs towards endothelial cells in
vitro [19] and may contribute to increased homing of EPCs to sites
of vascular injury.
Since changes in EPC number and function during statin
treatment generally occured without significant correlations
with LDL-cholesterol levels or statin-induced changes in LDL
serum levels [42] , it has been argued that the enhancement of
EPC’s functional activity by statins may represent a novel pleiotropic effect of statin therapy [52] . Of note, in a recent study, we
have observed that a 4-week statin treatment, but not ezetimibe
therapy, markedly increased functionally active EPCs in patients
with chronic heart failure, despite a similar change in LDL cholesterol levels, suggesting that, at least short-term effects of statin
treatment on EPCs are mediated by LDL cholesterol-independent
mechanisms [43] .
In conclusion, accumulating evidence suggests that statins
mobilize EPCs, increase their functional activity and, probably
their homing capacity to sites of vascular injury. These effects may
contribute to the endothelial-protective effects of statins and are
at least in part independent of their lipid-lowering properties.
Statins & EPC proliferation, differentiation & senescence
Several studies have suggested that statins increase proliferation,
migration and survival of EPCs derived from peripheral blood
[41,48–51] . Statins promote EPC differentiation and proliferation in
human peripheral blood mononuclear cells via the PI3K/Akt pathway (Figure 3) [41] , whereas differentiation of blood-derived mononuclear cells towards vascular smooth muscle progenitor cells may
be reduced by statins [48] . Ex vivo statin treatment of cultured early
EPCs increased expression of cell cycle-promoting proteins [49] , protected telomeres by induction of telomere repeat-binding factor-2
[50] and inhibited TNF α-induced apoptosis [51] , suggesting that
statins reduce EPC senescence and apoptosis, at least in vitro.
4
ACE inhibitors
There is emerging evidence suggesting that modulation of the
renin–angiotensin system by angiotensin-converting enzyme
(ACE)-inhibitors or angiotensin II type 1 receptor blockers
(ARBs) may have an impact on the number and functional activity of EPCs in different experimental and clinical settings.
Treatment with enalapril, an ACE-inhibitor, increased the
number of circulating EPCs in a murine hindlimb ischemia model
and improved incorporation of EPCs into sites of active neovascularization, associated with enhanced blood flow recovery in
ischemic hindlimbs [53] . These beneficial effects of enalapril were
accompanied by reduced stromal cell-derived factor (SDF)-1 concentrations in bone marrow, but higher SDF-1 levels in peripheral
blood of enalapril-treated mice, suggesting that reduced binding
of EPCs to SDF-1 in bone-marrow may contribute to their release
and mobilization after ACE-inhibition [53] . Of note, reduced
SDF-1 levels in bone marrow after ACE-inhibition may, at least
in part, result from increased bone marrow activation of dipeptidylpeptidase IV (DPP IV; CD26), a cell surface endopeptidase
cleaving chemokines such as SDF-1α [53] . Notably, blockade of
DPP IV by Diprotin-A, a DPP IV antagonist, prevented the effect
of enalapril on ischemia-induced EPC mobilization [53] .
Recently, treatment with another ACE-inhibitor, such as
perindopril, in rats alone or in combination with the diuretic
indapamide, restored both impaired levels and the angiogenic
capacity of circulating EPCs in a hindlimb ischemia model in
spontaneously hypertensive rats [54] . Moreover, in a small-scale
clinical trial, treatment with ramipril for 4 weeks improved both
number and functional activity of EPCs in patients with stable
coronary artery disease, suggesting that stimulation of EPCs
Expert Rev. Cardiovasc. Ther. 6(8), (2008)
Pharmacological approaches to improve endothelial repair mechanisms
Cardiovascular risk factors
(hypertension, dyslipidemia,
diabetes and smoking)
–
+
EPC mobilization
Review
Statins, ACE inhibitors, ARBs,
PPARγ agonists and EPO
Physical exersice
EPC repair capacity
(e.g., homing, migration
and paracrine effects)
+
of
–
Enhanced reendothelialization
Improved endothelial function
Direct
incorporation
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Paracrine
effects
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Diminished neointima formation
Development and progression
of atherosclerosis/restenosis
ho
Reendothelialization
Expert Rev. Cardiovasc. Ther. © Future Science Group Ltd (2008)
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Figure 2. Proposed effects of cardiovascular risk factors and pharmacological treatment approaches on mobilization and
functional repair capacity of EPCs. Cardiovascular risk factors have been shown to impair EPC mobilization from the bone marrow
and EPC repair capacity in terms of homing (i.e., adhesion, migration, invasion or release of growth factors) and differentiation. On the
other hand, several pharmacological therapies have been suggested to improve number and functional activity of EPCs in patients with
cardiovascular disease or diabetes. Enhancement of endogenous vascular repair mechanisms may potentially contribute to the overall
treatment effects of these drugs.
A
by ACE inhibitors may indeed contribute to beneficial vascular
effects of ACE inhibitor therapy in patients with coronary artery
disease [55] .
Angiotensin II type 1 receptor antagonists
Initial evidence that ARBs affect the number of circulating EPCs
was obtained in patients with Type 2 diabetes treated with olmesartan or irbesartan for 12 weeks [56] . Treatment with either of
these ARBs increased the number of EPCs in peripheral blood,
with a significant effect in the irbesartan group already apparent
after 4 weeks of therapy. Studies in spontaneously hypertensive
rats have shown that candesartan and losartan augment the number and colony formation capacity of circulating EPCs and exert
a favorable effect on EPC migration, at least in part by inhibiting
oxidant stress in EPCs, as measured by the thiobarbituric reactive
substances assay (TBARS) [57,58] .
Of note, bone-marrow-derived CD34 + hematopoietic progenitor
cells have been shown to express the angiotensin II type 1 receptor,
suggesting that direct effects of angiotensin II on progenitor cells are
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possible [59,60] . In line with this concept, Imanishi et al. [61] observed
that angiotensin II exerts detrimental effects on proliferation of
EPCs from healthy human subjects in vitro, diminished telomerase
activity and accelerated EPC senescence, possibly by induction of
gp91phox-mediated peroxynitrite formation in EPCs. However, in
a previous study from the same group, it was described that angiotensin II stimulated VEGFR-2 mRNA and protein expression in
human EPCs, resulting in enhanced VEGF-induced proliferation
of EPCs and vascular network formation in a matrigel assay [62] .
Hence, these studies seem to be at least partly contradictory and
provide evidence for both a stimulating and an inhibitory effect of
angiotensin II on the proliferative capacity of EPCs. This question
will therefore have to be clarified in further studies.
Other antihypertensive agents
Dihydropyridine calcium channel blockers
Recent in vitro observations have suggested that another group of
antihypertensive agents – calcium channel blockers – affect EPC
number and functional activity.
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Besler, Doerries, Giannotti, Lüscher & Landmesser
β-blockers nebivolol & carvedilol
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Several studies have suggested that carvedilol and nebivolol
directly improve endothelial function, that is, they increase nitric
oxide bioavailability and augment endothelium-dependent vasodilation in patients with coronary artery disease and essential
hypertension [65,66] .
In a recent study in C57BL/6 mice with extensive anterior myocardial infarction we have observed an improvement in endothelial function of aortic ring segments and an increase in the number
of circulating EPCs after 4 weeks of treatment with nebivolol,
whereas metoprolol succinate did not augment EPC levels during
the treatment period, consistent with the notion that nebivolol
may exert effects on EPCs independent of its β1-receptor blocking
effect [C Dörries & U L andmesser ; Unpublished Data] .
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Antidiabetic medication
We and others have shown that EPC number and functional
activity, such as migration, tube formation and re-endothelialization capacity, are substantially impaired in patients with diabetes
mellitus [18,28,67–69] . Several recent studies have suggested that
treatment with the PPAR-γ-agonists rosiglitazone and pioglitazone increases EPC number and functional activity, likely at
least in part independent of their effects on glucose [18,70–73] . In
addition, recent in vitro data suggest that insulin exerts an effect
on EPC function via activation of the IGF-1 receptor [74] ; however, whether this occurs in diabetic patients treated with insulin
remains to be determined.
Thiazolidinediones: PPAR-γ agonists
PPAR-γ agonists, such as rosiglitazone or pioglitazone, favorably
influence glucose homeostasis by interfering with both adipogenesis and insulin resistance. In addition, PPAR-γ agonists have
6
been shown to reduce vascular inflammation, improve endothelial
function and inhibit neointima formation [75,76] . A growing body
of evidence suggests that vascular effects of PPAR-γ agonists are
probably mediated by direct effects on vascular cells [75,76] and,
as described later, on progenitor cells.
Several studies have observed that both rosiglitazone and pioglitazone increase the number and functional activity of EPCs
[18,70–73] . In an uncontrolled clinical study it was suggested that
rosiglitazone therapy increased the number and in vitro migratory activity of circulating early EPCs [71] . We have observed in a
prospective, randomized, placebo-controlled study that 2 weeks
of therapy with rosiglitazone increased the number and in vivo
re-endothelialization capacity of EPCs derived from patients
with diabetes [18] . Pioglitazone therapy has been reported to
increase the number, migratory and adhesion capacity of EPCs
in patients with Type 2 diabetes after 8 weeks of therapy [72] .
Moreover, incubation of diabetic EPCs with pioglitazone
increased EPC proliferation and attenuated EPC apoptosis during ex vivo culture [72,73] .
Notably, rosiglitazone therapy reduced superoxide production
and increased nitric oxide production by EPCs derived from diabetic patients [18] . Furthermore, rosiglitazone treatment reduced
NAD(P)H oxidase activity of EPCs from diabetic patients, representing a potential novel mechanism whereby PPAR-γ agonism
promotes vascular repair [18] . In experiments using siRNA, we
have observed that the effects of rosiglitazone on EPC nitric oxide
availability and oxidative stress were mediated via the PPAR-γ
receptor [18] .
Moreover, ex vivo exposure of human peripheral blood mononuclear cells to rosiglitazone increased colony formation and likely
promoted differentiation towards the endothelial lineage, whereas
differentiation toward the smooth muscle cell lineage may be
reduced [70] .
In mice, treatment with pioglitazone for 10 days upregulated
Sca1+/VEGFR-2 + EPCs in peripheral blood and bone marrow as
well as the number of ex vivo cultured spleen-derived EPCs [73] .
The increase in EPC number was accompanied by augmented
vessel growth in a subcutaneously implanted polyvinyl sponge and
improved migratory capacity of EPCs in vitro [73] . Furthermore,
ex vivo pioglitazone treatment of EPCs increased expression of
telomere repeat-binding factor 2 and prevented apoptosis induction in EPCs [73] .
Several recent meta-analyses have suggested that pioglitazone
therapy reduce cardiovascular risk more than rosiglitazone therapy [77,78] . Whereas both PPAR-γ agonists exert similar effects on
endothelial progenitor cells, rosiglitazone therapy probably has a
less favorable effect on the lipid profile [79] , which may be relevant
for a potentially less favorable overall effect on clinical outcome.
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Ex vivo treatment of murine mononuclear cells with benidipine, a dihydropyridine-calcium channel blocker, increased the
number of early EPCs after 7 days of culture [63] . Simultaneous
treatment with wortmannin, a PI3K inhibitor, attenuated the
effects of benedipine on cultured EPCs, suggesting that the PI3K
pathway is involved. Moreover, incubation of EPCs with benidipine promoted Akt phosphorylation, further suggesting a role
for the PI3K/Akt pathway in producing the observed effects of
benidipine on early EPCs (Figure 3) [63] .
Nifedipine – a dihydropyridine-calcium channel blocker
capable of stimulating manganese superoxide dismutase
(MnSOD) expression in mature endothelial cells – enhanced
VEGF release from EPCs, improved migratory capacity of EPCs
in a Boyden chamber system as well as adhesion capacity on
TNF-α activated human umbilical vein endothelial cells [64] .
Nifedipine increased MnSOD expression in EPCs and siRNAinduced knockdown of MnSOD abolished the beneficial effects
of nifedipine on EPC migratory capacity, suggesting a role of
this antioxidant enzyme system for the effects of nifedipine on
EPCs. At present, however, no data on the effect of calcium
channel antagonist therapy on in vivo EPC number and function have been published.
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Review
Insulin
An inital in vitro study has suggested that treatment of peripheral
blood mononuclear cells with insulin dose-dependently increases
the formation of EPC colony forming units and improves the
tube formation capacity of EPCs, an effect that was in part
mediated through extracellular signal-related kinase 1/2 and
Expert Rev. Cardiovasc. Ther. 6(8), (2008)
Pharmacological approaches to improve endothelial repair mechanisms
EPO & its analogs
Lipid-modifying therapies
• Statins
Inhibitors of the renin-angiotensin system
• Angiotensin-converting enzyme inhibitors
• Angiotensin II type 1 receptor blocker
Other antihypertensive drugs
• Dihydropyridine calcium channel blocker
• b -blockers: carvedilol and nebivolol
Antidiabetic medications
• PPAR- g agonists: pioglitazone and rosiglitazone
• Insulin
Other
• Erythropoietin
eNOS phosphorylation and NO bioavailiability in EPO-treated
cells (Figure 3) [86] . The effects of EPO treatment on vascular
repair processes may depend, at least in part, on the vascular
EPO receptor system, since VEGF expression, mobilization
of EPCs, microvascular growth and blood flow recovery were
impaired after femoral artery ligation in wild-type, bone-marrow transplanted EPO receptor knockout mice [87] . Moreover,
EPO treatment for 14 days failed to increase CD34 + hematopoietic stem and progenitor cell numbers in eNOS-deficient mice,
underlining the role of eNOS-derived NO for EPO-mediated
mobilization of progenitor cells [88] .
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Originally, erythropoietin (EPO) was described as a hematopoietic cytokine, regulating proliferation and differentiation of
erythroid precursor cells. However, several studies have suggested
that EPO confers several antiapoptotic and anti-inflammatory
effects in cardiac, renal and neuronal cells, beyond regulation of
hematopoiesis.
Bahlmann et al. demonstrated, in patients with renal anemia and healthy subjects, that treatment with very low doses
of recombinant human EPO and darbepoetin α, a recombinant EPO analog, increases the number of circulating CD34 +
hematopoietic stem cells as well as the number and function of
ex vivo cultured EPCs [81,82] . Heeschen et al. demonstrated that
erythropoietin treatment increases the number and proliferation of bone-marrow derived EPCs, which was accompanied
by improved neovascularization in a murine hindlimb ischemia
model [83] . To test the relevance of their findings in humans,
the authors isolated bone marrow-resident and circulating EPCs
from patients with angiographically documented coronary artery
disease and detected EPO serum levels. Of note, EPO serum
levels correlated with the number and function of EPCs isolated
from both bone marrow and peripheral blood, further suggesting that EPO may regulate EPCs in vivo [83] .
Likewise, in patients with a first acute myocardial infarction, a
single bolus injection of darbepoetin‑α before primary coronary
intervention potently increased EPC number in peripheral blood
[84] , whereas chronic EPO treatment of patients with congestive
heart failure for a mean period of 28 months, failed to increase
levels of hematopoietic progenitor cells in peripheral blood, but
augmented proliferation of ex vivo cultured EPCs [85] .
Initial results suggesting that EPO-induced increases of circulating EPCs exert beneficial effects on vascular repair processes, were obtained in a wire injury model of the femoral
artery in mice [86] . Injection of recombinant human EPO for
3 days after induction of injury augmented levels of circulating EPCs, accelerated re-endothelialization of denudated areas
of the femoral artery and inhibited neointima formation [86] .
Mechanistically, EPO treatment affected the differentiation
of circulating bone marrow-derived EPCs and proliferation of
mature resident endothelial cells located next to the mechanical
injury, which might in part be explained by an increase in Akt/
Box 1. Pharmaceutical agents that may increase
number and functional activity of endothelial
progenitor cells.
of
protein-kinase 38 [74] . Neutralizing antibodies and antisense
oligonucleotides against the insulin receptor had no effect on
EPC outgrowth, whereas inhibition of human IGF-1 receptor
by neutralizing antibodies abrogated the insulin-induced effects
on EPC number and function, suggesting that insulin exerts
effects on EPCs via the IGF-1 receptor [74] . Whether this is also
observed in diabetic patients treated with insulin remains to be
determined. Initiation of insulin therapy in diabetic patients
has been shown to increase the number of circulating CD34 +/
CD133 + hematopoietic progenitor cells in peripheral blood of
patients with poorly controlled Type 2 diabetes mellitus after
a mean time of 5.4 weeks [80] ; however, further information is
required.
Review
www.expert-reviews.com
HDL & EPCs
HDL-targeted therapies are currently intensely studied as a
potential novel therapeutic option in patients with cardiovascular
disease. Besides promoting reverse cholesterol transport, HDL
may exert direct vasoprotective effects [89] . In animal models,
infusion of reconstituted HDL has been shown to increase the
number of Sca-1+ hematopoietic stem cells, to promote endothelial repair in the thoracic aorta from apoE knockout mice and
to augment angiogenesis in a murine hindlimb ischemia model
[90,91] . Similarly, increased HDL levels induced by adenoviral
transfer of human apolipoprotein (apo) A-I, the major structural HDL apo, improved both EPC number and function, and
enhanced endothelial repair of transplanted carotid allografts
in mice [92] .
Pharmacological effects of apoA-I mimetics, such as D-4F, on
reverse cholesterol transport and HDL-induced vasoprotective
effects, are currently being evaluated. In a rat model of diabetes,
long-term treatment with D-4F increased the number of EPC
colonies in vitro and the expression of eNOS and heme oxygenase-1 in ex vivo cultured EPCs, suggesting a beneficial effect of
D-4F on the proliferative and antioxidant capacity of EPCs in
the diabetic state [93] . A first small clinical study in humans suggested that infusion of reconstituted HDL augments the number
of CD34 +/VEGFR-2 + cells in peripheral blood of patients with
Type 2 diabetes, 1 week after administration [94] .
7
Review
Besler, Doerries, Giannotti, Lüscher & Landmesser
Five-year view
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
A
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Expert commentary
Since the initial description of putative bone-marrow-derived
endothelial progenitor cells in human peripheral blood in 1997,
numerous studies have suggested that circulating bone marrowderived EPCs promote re-endothelialization after vascular injury
and ischemia-induced neovascularization. Importantly, patients
with cardiovascular risk factors or coronary disease have, in most
studies, a reduced number and functional capacity of EPCs as
compared to healthy subjects, suggesting that cardiovascular risk
factors do not only directly alter vascular endothelial function, but
also impair the endothelial repair capacity mediated by circulating progenitor cells. Notably, several pharmacological treatment
approaches, such as statin therapy, PPAR-γ, ACE-inhibitors and
ARB therapy, likely have a direct impact on circulating progenitor
cells, that may contribute to their overall effects on the vascular wall. Furthermore, several pharmacological agents may help
to optimize cell-based treatment approaches in cardiovascular
medicine, given the significant impairment of autologous, patientderived progenitor cells currently used in clinical studies.
Endothelial progenitor cells are currently assessed by several
methods, including FACS analysis of peripheral blood, using
markers such as CD34 and KDR, culture and/or colony-forming
assays of blood-derived mononuclear cells and by transplantation of culture-derived EPCs into nude mouse models. There
is a growing consensus that there are likely several subsets of
EPCs. ‘Early’ EPCs are most likely derived from CD14 + cells,
are obtained after short-term culture of mononuclear cells and
act largely by paracrine effects, whereas ‘late’ EPCs may transdifferentiate into endothelial cells, i.e., may incorporate into
the endothelial layer, but are substantially lower in numbers.
Within the next years our understanding of the definition and
functional role of subsets of EPCs will hopefully improve and we
will learn more about mechanisms leading to their ‘dysfunction’
in cardiovascular disease. EPCs may represent an interesting
therapeutic target for pharmaceutical strategies, but also for
cell-based therapies of vascular and cardiac disease. However,
the mechanisms whereby drug therapy alters number and function of circulating EPCs will have to be determined in more
detail. In particular, the impact of pharmacological agents on
direct incorporation of EPCs into the endothelial monolayer
and the release of paracrine mediators by EPCs will have to be
characterized. In addition, studies comparing effects of different
pharmacological agents from the same class of drugs on EPC
number and function, are of interest to detect potential differences between pharmacophores. Research on EPCs will likely
lead to novel developments in the field of bioengineering, such as
bioengineered stents and autologous ‘living’ heart valves [97] .
of
Ex vivo treatment of human EPCs with either
sphingosine-1-phosphate (S1P), an HDL-associated lysophospholipid, or its synthetic analog FTY720, improved blood flow
after transplantation of EPCs in a murine hindlimb ischemia
model, at least in part via S1P3 receptor-induced phosphorylation
of the CXCR4 receptor [95] . Of note, CXCR4 receptor signaling
is critical for the repair capacity of EPCs and is involved in homing, migration and functional integration of progenitor cells in
ischemic tissues, suggesting a possible mechanism whereby HDL
may exert its beneficial effects on functional activity of EPCs. In
addition, HDL may increase the number of EPCs in peripheral
blood by inhibiting EPC apoptosis, since incubation of isolated
human EPCs with pooled HDL from healthy donors attenuated
homocysteine-induced caspase-3 activity in vitro, whereas eNOS
expression in EPCs increased in the presence of HDL derived from
healthy donors [96] . Thus, raising HDL with beneficial vascular
effects or apoA-I may increase the repair capacity of EPCs.
Key issues
• Functional and structural disruption of the endothelium is thought to play a critical role in development and complications of
atherosclerotic vascular disease and restenosis after percutaneous coronary interventions.
• Accumulating evidence suggests that endothelial progenitor cells (EPCs) promote re-endothelialization of injured arteries and ischemiainduced neovascularization.
• Notably, recent studies have suggested that number and functional repair capacity of circulating EPCs are profoundly reduced in
patients with cardiovascular risk factors or established cardiovascular disease.
• Several pharmacological agents have been suggested to increase number and/or functional activity of EPCs that may play a role in their
therapeutic effects, such as statins, PPAR-γ-agonists, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and
erythropoietin.
• In addition, in vitro data have suggested that dihydropyridine calcium channel blockers, insulin and reconstituted HDL increase
functional activity of EPCs.
• The mechanisms whereby drug therapy alters EPC number and function will have to be determined in more detail, but likely include
effects on the PI3-kinase-Akt-endothelial nitric oxidesynthase pathway.
• Several pharmacological agents may play a role for optimization of cell-based treatment approaches in the cardiovascular field, for
example by improving the functional and homing capacity of autologous patient-derived progenitor cells.
8
Expert Rev. Cardiovasc. Ther. 6(8), (2008)
Pharmacological approaches to improve endothelial repair mechanisms
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Affiliations
•
Christian Besler, MD
Cardiovascular Center, University Hospital
Zurich; and, Cardiovascular Research,
Institute of Physiology; and, Center for
Integrative Human Physiology, University
of Zurich, Switzerland
Tel.: +41 446 355 097
Fax: +41 446 356 827
[email protected]
11
•
Giovanna Giannotti, MD
Cardiovascular Center, University Hospital
Zurich; and, Cardiovascular Research,
Institute of Physiology, University of
Zurich, Zurich, Switzerland
Tel.: +41 446 355 081
Fax: +41 446 356 827
[email protected]
•
Thomas F Lüscher, MD
Cardiovascular Center, University Hospital
Zurich; and, Cardiovascular Research,
Institute of Physiology, University of
Zurich, Zurich, Switzerland
Tel.:+41 442 552 121
Fax: +41 442 554 251
[email protected]
•
Ulf Landmesser, MD
Cardiovascular Center, University Hospital
Zurich, Raemistrassse 100, 8091 Zurich,
Switzerland
Tel.: +41 442 559 595
Fax: + 41 442 554 251
[email protected]
ro
Carola Doerries, MD
Cardiovascular Center, University Hospital
Zurich; and, Cardiovascular Research,
Institute of Physiology, University of
Zurich, Zurich, Switzerland
Tel.: +41 446 355 097
Fax: +41 446 356 827
[email protected]
A
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•
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Besler, Doerries, Giannotti, Lüscher & Landmesser
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Review
12
Expert Rev. Cardiovasc. Ther. 6(8), (2008)