ATVB in Focus
Diabetes and Mechanisms of Ineffective Vascular Repair
Series Editors: Ann Marie Schmidt and Chantal Boulanger
Specific Role of Impaired Glucose Metabolism and
Diabetes Mellitus in Endothelial Progenitor Cell
Characteristics and Function
Kai-Hang Yiu, Hung-Fat Tse
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Abstract—The disease burden of diabetes mellitus (DM) and its associated cardiovascular complications represent a growing
and major global health problem. Recent studies suggest that circulating exogenous endothelial progenitor cells (EPCs)
play an important role in endothelial repair and neovascularization at sites of injury or ischemia. Both experimental
and clinical studies have demonstrated that hyperglycemia related to DM can induce alterations to EPCs. The reduction
and dysfunction of EPCs related to DM correlate with the occurrence and severity of microvascular and macrovascular
complications, suggesting a close mechanistic link between EPC dysfunction and impaired vascular function/repair in DM.
These alterations to EPCs, likely mediated by multiple pathophysiological mechanisms, including inflammation, oxidative
stress, and alterations in Akt and the nitric oxide pathway, affect EPCs at multiple stages: differentiation and mobilization
in the bone marrow, trafficking and survival in the circulation, and homing and neovascularization. Several different
therapeutic approaches have consequently been proposed to reverse the reduction and dysfunction of EPCs in DM and
may represent a novel therapeutic approach to prevent and treat DM-related cardiovascular complications. (Arterioscler
Thromb Vasc Biol. 2014;34:1136-1143.)
Key Words: diabetes mellitus
D
iabetes mellitus (DM) is a complex metabolic disorder
characterized by impaired glucose metabolism with
hyperglycemia. Patients with DM have a 2- to 4-fold increased
risk of developing cardiovascular complications compared
with nondiabetic controls.1 This has been attributed to the
occurrence of endothelial dysfunction that leads to the initiation and progression of atherosclerotic vascular disease2 and
impaired neovascularization after ischemia induced by hyperglycemia.3,4 In patients with impaired glucose metabolism
and DM, the vascular endothelium is challenged by inflammation, reactive oxygen species, and deletion of endothelial
nitric oxide synthase (eNOS) with resultant endothelial dysfunction.2,5–7 The depletion and dysfunction of the circulating
endothelial progenitor cells (EPCs) are thought to underlie the
endothelial dysfunction in DM. In this review, the possible
mechanisms, functional consequences, and the potential therapeutic approach for impaired EPCs in DM are discussed. A
systematic literature search for full-text papers in the English
language was performed using MEDLINE, Embase, and the
Cochrane library through to February 2014. In the search
phrases used, the following terms were combined with the
phrase AND Diabetes: endothelial progenitor cells, cardiovascular disease, myocardial infarction, and stroke.
Please see http://atvb.ahajournals.org/site/misc/
ATVB_in_Focus.xhtml for all articles published
in this series
Alterations of EPCs in DM
EPCs were initially described as a pool of circulating bone marrow (BM)–derived CD34+ progenitor cells that display vasculogenic potential.8,9 In response to stimuli such as exercise, tissue
ischemia, and cytokines, EPCs can be mobilized from the BM
into the peripheral circulation and contribute to endothelial repair
and neovascularization at sites of injury/ischemia (Figure 1A).
Circulating EPCs are mainly defined and enumerated using flow
cytometry or colony-forming unit assay by their expression of
a panel of surface markers such as CD34, CD133, and kinase
insert domain receptor (KDR).10 Nevertheless, there is significant overlapping in the results of these assays for EPCs and
hematopoietic progenitor cells. Furthermore, 2 major subtypes
of EPCs, early and late EPCs, can be isolated from circulating
Received on: January 8, 2014; final version accepted on: April 2, 2014.
From the Division of Cardiology, Department of Medicine, Queen Mary Hospital (K.-H.Y., H.-F.T.) and Shenzhen Institute of Research and Innovation
(H.-F.T.), University of Hong Kong, Hong Kong, China; and Research Centre of Heart, Brain, Hormone, and Healthy Aging (K.-H.Y., H.-F.T.) and Hong
Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine (H.-F.T.), Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong
Kong, China.
The online-only Data Supplement is available with this article at http://atvb.ahajournals.org/lookup/suppl/doi:10.1161/ATVBAHA.114.302192/-/DC1.
Correspondence to Hung-Fat Tse, MD, Cardiology Division, Department of Medicine, University of Hong Kong, Room 1928, Block K, Queen Mary
Hospital, 102 Pokfulam Rd, Hong Kong Special Administrative Region, Hong Kong, China. E-mail [email protected]
© 2014 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org
1136
DOI: 10.1161/ATVBAHA.114.302192
Yiu and Tse Diabetes Mellitus and Endothelial Progenitor Cells 1137
Nonstandard Abbreviations and Acronyms
BM
DDP-4
DM
eNOS
EPC
SDF-1α
VEGF
bone marrow
dipeptidyl peptidase 4
diabetes mellitus
endothelial nitric oxide synthase
endothelial progenitor cell
stromal-derived factor 1α
vascular endothelial growth factor
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mononuclear cells using different culture durations and protocols.10–12 Both early and late EPCs are derived from circulating
mononuclear cells and may have their distinct role in endothelial
repair and vasculogenesis. In brief, early EPCs that emerge after
4 to 7 days of culture originate from the hematopoietic lineage
with a limited proliferative potential although they contribute to
in vivo neovascularization via secretion of proangiogenic cytokines. Late EPCs appear after 1 to 3 weeks in culture and express
CD34 as well as other endothelial markers, such as KDR and
CD146. They have a potent proliferative capacity to form mature
endothelial cells in vitro. In contrast to early EPCs, late EPC cultures are more difficult to establish and sometimes impossible in
some patients with DM and cardiovascular disease.13
Many clinical studies have demonstrated that number of circulating EPCs is reduced and their function impaired in terms of
decreased proliferation, adhesion, and vasculogenesis in patients
with type 1 and type 2 DM (Table I in the online-only Data
Supplement). Similar alterations in EPCs are observed in patients
with type 1 and type 2 DM, suggesting a close mechanistic link
between hyperglycemia and the reduction and functional impairment of EPCs. Indeed, the reduction in circulating EPCs seems to
correlate with glycemic control or severity of impaired glucose tolerance in subjects with or without established DM, respectively.14–20
Similarly, the deleterious effects of hyperglycemia on the number
and function of late EPCs have also been reported. Late EPCs were
found in an activated state in patients with DM.21 In vitro hyperglycemia or a diabetic intrauterine environment diminished late EPC
colony formation, self-renewal capacity, and capillary-like tube
formation.22 Moreover, decreased secretion of NO and vascular
endothelial growth factor (VEGF), reduced activity of superoxide dismutase, and impaired function, such as migration and tube
formation, are observed in activated late EPCs after exposure to a
hyperglycemic condition23 or advanced glycation end products.24
Reduced number and function of EPCs are also more
prevalent in patients with type 1 and type 2 DM with diabetic
nephropathy25–28 and macrovascular26,29–33 complications and
correlate with the degree of atherosclerosis.34 These observations suggest that the burden of DM-related cardiovascular complications correlates with the number and function of
EPCs: alterations in EPCs may contribute to the development
and progression of atherosclerosis in patients with DM. This
has been attributed to the decreased number of EPCs as well
as impairment of their function and recruitment to injured
vasculature, causing defective endothelial repair and neovascularization (Figure 1A). This has been confirmed by experimental studies (Table II in the online-only Data Supplement)
wherein EPCs from patients with DM35 as well as an animal
model of DM exhibited impaired re-endothelialization of an
injured artery36 and limited ability to enhance neovascularization in ischemic tissue.37–39
In contrast, a biphasic pattern in the change of EPCs has
also been observed: a decreased number of EPCs seen in
nonproliferative retinopathy40,41 but an increased number and
clonogenic potential in patients with DM with proliferative
retinopathy.40,42,43 In patients with type 1 DM and early nonproliferative diabetic retinopathy, only dysregulation of late EPCs
with increased clonogenic potential but impairment of homing
mechanism is observed.44 Similarly, functional impairments of
EPCs are observed in patients with type 140 and type 243 DM
with proliferative retinopathy despite an increase in their number and clonogenic potential. It is likely that the clonogenic
potential and thus the number of late EPCs increased with the
progression from nonproliferative to proliferative retinopathy.
Furthermore, the proangiogenic activities of increasing number of dysfunctional EPCs may contribute to the pathological
retinal neovascularization in late-stage diabetic retinopathy.
In addition to neovascularization, EPCs are involved in
thrombus recanalization.45 It has been demonstrated that the
presence of late EPCs has both anticoagulant and antifibrinolytic properties.46 Indeed, hyperglycemia may reduce plasminogen activator inhibitor-1 secretion and, therefore, diminish
the antifibrinolytic property of EPCs.23,24 Such an impairment
of EPC properties may further explain the occurrence of macrovascular complications in patients with DM.
Mechanisms of Alteration of EPCs in DM
Several major mechanisms have been proposed to explain
the reduced number and dysfunction of EPCs associated
with impaired glucose metabolism and DM. The underlying
mechanisms by which hyperglycemia and insulin resistance
can induce inflammation, oxidative stress, and deletion of NO
have been extensively summarized in other reviews.2,5–7,47,48
Moreover, primary or secondary dyslipidemia in patients
with DM can also interact with hyperglycemia and insulin to
induce EPC dysfunction. In the following section, the deleterious effects of these mechanisms that affect EPCs at multiple
stages of their lifecycle are discussed (Figure 1B).
Differentiation and Mobilization
Both human and animal studies have demonstrated that DM
is associated with pathological changes in the BM, including
microangiopathy with microvascular rarefaction, autonomic
neuropathy, alteration of the vascular/osteoblastic progenitor niche, and depletion of hematopoietic tissue and the stem
cell pool.49–53 Although these abnormalities might not cause
a major defect in hematopoiesis, they are associated with
reduced differentiation and release of EPCs. Experimental50,51
and human studies54,55 also demonstrate that DM impairs the
mobilization of EPCs in response to tissue ischemia or cytokines, such as granulocyte colony-stimulating factor. Among
the several different mechanisms, eNOS dysfunction56 and
altered cytokine gradients, for example, stromal-derived factor
1α (SDF-1α) between the BM and ischemic tissues in DM,50,55
may play major roles in the impairment of EPC mobilization.
SDF-1α is a cytokine that contributes to EPC mobilization by
stimulating chemokine receptor type 4 (CXCR4) on the cell
1138 Arterioscler Thromb Vasc Biol June 2014
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Figure 1. A, Potential functional
role of endothelial progenitor cells
(EPCs) in vascular repair in normal
subjects (top) and in patients with
diabetes mellitus (DM; bottom). In
subjects with DM, the number of
bone marrow (BM) progenitor cells
and their mobilization are reduced
because of the alteration in the
osteoblastic and vascular niches
and the cytokines profiles, respectively, and the survival of circulating EPCs is reduced. As a result,
the numbers of circulating EPCs
are decreased in subjects with
DM. Furthermore, the migratory,
recruitment, and angiogenic functions of EPCs at ischemic tissue
in subjects with DM are impaired
and thus contribute to defective
vascular repair and angiogenesis. B, Potential mechanisms of
impairment of the number and
function of EPCs in DM induced by
hyperglycemia and insulin resistance. Multiple pathophysiological
mechanisms, including changes in
inflammatory signals (eg, nuclear
factor-κB [NFkB], interleukin 8),
oxidative stress (eg, reactive oxidative species [ROS], thrombospondin 2 [TSP-2], and advanced
glycation end products [AGEs]),
nitric oxide (eg, endothelial nitric
oxide synthase [eNOS]), and Akt
signal pathway, affect EPCs at
multiple stages during their lifetime: differentiation and mobilization in BM, trafficking and survival
in the circulation, and homing
and neovascularization. G-CSF
indicates granulocyte colony-stimulating factor (CSF); SCF, stem cell
factor; SDF-1, stromal-derived factor 1; and VEGF, vascular endothelial growth factor.
membrane of EPCs.57 In DM, the increased BM SDF-1α level
resulting from enhanced CD26/dipeptidyl peptidase 4 (DPP4) activity and the decreased production of SDF-1α in the
ischemic tissue lead to a reduced gradient of this chemoattractant to mobilize EPCs from BM to the circulation.38,50,54 One of
the mechanisms of action of granulocyte colony-stimulating
factor is via the cleavage of SDF-1α through the release of
protease CD26/DDP-4 to reduce the local level of chemoattractant and thus mobilize stem cells from the BM. As a result,
the increased BM SDF-1α level in DM reduces the ability of
granulocyte colony-stimulating factor to mobilize stem cells,
including EPCs, from the BM.
Trafficking and Survival
As discussed above, the migration of EPCs to sites of injury/
ischemia is mediated by the gradient of SDF-1α and other
chemoattractants, such as VEGF and erythropoietin. In addition to the altered cytokine gradient, decreased NO, increased
reactive oxygen species, and advanced glycation end products
in DM impair this migration.39,50,52 These pathological processes induced by DM also increase apoptosis and decrease
proliferation of EPCs. Both in vitro and in vivo studies have
shown that hyperglycemia and its associated lipotoxicity
with elevated oxidized low-density lipoprotein increases the
senescence or apoptosis of EPCs mediated through multiple
Yiu and Tse Diabetes Mellitus and Endothelial Progenitor Cells 1139
different molecular pathways, including interleukin 8, Akt,
protein kinase C, and p38 mitogen-activated protein kinase
(Figure 1B).47,48,50,58,59
Homing and Neovascularization
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It has been postulated that homing circulating EPCs to sites of
ischemia can contribute to vascular repair by direct transdifferentiation into vascular endothelial cells and indirectly via the
secretion of proangiogenic cytokines.8–11 As discussed above,
the local release and thus the gradient of cytokines, especially
SDF-1α, play a pivotal role in EPC homing. The blockade
of either SDF-1α or its receptor CXCR4 prevents the recruitment of EPCs to injured sites.57 In patients with DM, the high
glucose environment reduces the level of VEGF and SDF-1
secretion from endothelial cells via the hypoxia-inducible factor/hypoxia-responsible element pathway and DDP-4 activity.50 The reduced level of these cytokines may then impair
the regulation of growth, migration, and survival of EPCs.
Alternatively, exogenous administration of SDF-1α reversed
the DM-induced EPC dysfunctional homing (Figure 2) and
improved neovascularization and wound healing in animal
models.56 In vitro culture of EPCs from patients with DM35,60
or from healthy subjects with a high glucose level61 as well as
EPCs from animal models of DM36,49,62,63 exhibited impaired
proliferation and angiogenesis. Similarly, multiple different
molecular mechanisms related to hyperglycemia as discussed
above have been proposed to explain the functional impairment and reduced survival of EPCs recruited to the sites of
ischemia (Figure 1B).47,48,50 More recently, altered expression
of microRNA, such as microRNA 126 and microRNA 130a,
has been implicated in EPC dysfunction mediated through
extracellular signal–regulated kinase, VEGF, and the phosphoinositide 3-kinase/Akt/eNOS signal pathway.64,65
Therapeutic Avenues to Restore EPC
Alterations in DM
As summarized in Figure 2, several different approaches have
been investigated to restore the dysregulation and dysfunction
of EPCs mediated by DM.
Antidiabetic Agents
Because impaired glucose metabolism with hyperglycemia is the
primary initiating event that induces EPC alteration in DM, and
EPC dysfunction is closely related to the degree of hyperglycemia,
improved hyperglycemic control should be the initial therapeutic
target. Indeed, the severity of hyperglycemia seems to be negatively correlated with EPC number and function in patients with
DM.14–20 In an animal model of type 1 DM, successful restoration
of normoglycemia by islet transplantation increased the number
of EPCs and improved their angiogenic function.66 Currently,
there are only limited data on the optimal antidiabetic therapy
to reverse EPC dysfunction in DM. Insulin therapy improves the
clonogenic potential of EPCs in vitro67 and increases the number of EPCs in patients with type 2 DM.68 Metformin improved
glycemic control and increased the number of EPCs in patients
with type 2 DM.69 Nonetheless, add-on sulfonylureas (gliclazide)
to metformin70 or thiazolidinediones71 were more effective than
metformin alone in increasing circulating EPCs in patients with
type 2 DM despite similar glycemic control.
In addition to the hypoglycemic effect, thiazolidinediones have been shown to increase EPC production, reduce
EPC apoptosis, and enhance their migratory capacity and reendothelization of injured artery via the activation of the Akt/
eNOS pathway, as well as anti-inflammatory and antioxidative actions.28,35,59,72
Glucagon-like peptide-1 agonist and DPP-4 inhibitors are
a newer class of antidiabetic agents that act by increasing the
Figure 2. Potential therapeutic
avenues to restore endothelial
progenitor cell (EPC) number
and functions for the prevention of macrovascular and
microvascular complications
in diabetes mellitus (DM). ACEI
indicates angiotensin-converting enzyme inhibitor; ARB,
angiotensin receptor blocker;
CAD, coronary artery disease;
DDP-4, dipeptidyl peptidase 4;
EPO, erythropoietin; G-CSF,
granulocyte colony-stimulating
factor; miR, microRNA; PVD,
peripheral vascular disease;
and TZD, thiazolidinedione.
1140 Arterioscler Thromb Vasc Biol June 2014
incretin level to inhibit glucagon release and thus increase
insulin secretion. Experimental studies show that the glucagon-like peptide-1 agonist73 and DPP-4 inhibitor (sitagliptin)74
improve the function of EPCs in DM. Interestingly, in patients
with type 2 DM, DDP-4 inhibitor increased the plasma level
of SDF-1α via the suppression of its degradation by CD26/
DDP-4 activity and thus enhanced EPC mobilization from the
BM as discussed above.75 In contrast, there is potential concern
in the application of these incretin-based therapies to mobilize
EPCs in patients with DM. Recent human studies suggested
that DDP-4 inhibitor (sitagliptin) or glucagon-like peptide-1
agonist (exenatide) can induce marked β-cell hyperplasia and
increase the prevalence of preneoplastic lesions.76 The mobilization of BM EPCs by these incretin-based therapies may
promote pancreatic tumor angiogenesis and growth in vivo.77
Approaches to Restore BM Mobilization
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Other than DDP-4 inhibitor, increased mobilization of EPCs
from the BM in DM can be achieved by the administration
of granulocyte colony-stimulating factor or erythropoietin,
as well as the blockade of CXCR4 receptor in the BM using
AMD3100 (Mozobil). This decreases the binding of SDF1α to reduce the retention of EPCs.78 Previous clinical studies suggest that daily thiamine intake is associated with the
level of circulating EPCs in patients with type 2 DM; thus,
thiamine deficiency may be linked to impaired EPC mobilization.79 Experimental studies have demonstrated that treatment
with benfotiamine, a liposoluble vitamin B1 with much higher
bioavailability compared with thiamine, can reduce oxidative stress and activate the Akt/eNOS pathway to restore EPC
number and their mobilization in BM.11,49
γ-Tocotrienol, a vitamin E isoform, has also been shown
to enhance mobilization of EPCs via increased expression of
VEGF.80 Whether these vitamin supplements can restore the
EPC number and function and thus improve vascular function
in patients with DM requires future study.
Approaches to Improve EPC Function and Survival
Several other therapeutic approaches or agents that are commonly used in patients with DM to prevent or treat cardiovascular disease can also improve EPC number and function
via different mechanisms. In addition to their lipid-lowering
effect, statins have many pleiotropic effects that may explain
their cardiovascular benefit. Both experimental81,82 and clinical studies83 demonstrate that statins increase the number and
function of circulating EPCs by increasing the bioavailability
of NO and reducing oxidative stress and apoptosis of EPCs.
Blockade of the renin–angiotensin system with angiotensinconverting enzyme inhibitors or angiotensin receptor blockers has also been shown to increase EPC number in patients
with DM,84,85 possibly mediated by their anti-inflammatory
and antioxidative actions through the suppression of angiotensin II.86 In addition, a combination of statin and angiotensin
receptor blocker seems to have a synergistic effect to increase
the number and function of EPCs in DM.85,87 Lifestyle modifications, including exercise88 and weight reduction,89 have also
been shown to increase EPC number and function in patients
with cardiovascular disease or DM.
Biological Therapies
Several different biological therapies that target the pathophysiological mechanisms of DM-mediated EPC dysfunction have
been proposed. Several strategies by priming EPCs have been
proposed to improve the function of EPCs in diabetic condition.
The use of placenta growth factor has been shown to enhance
EPC differentiation and improve postischemic neovascularization in diabetic mice.90 Pretreatment of EPCs with proangiogenic growth factors, including VEGF, basic fibroblast growth
factor, and platelet-derived growth factor, improves incisional
wound healing (as assessed by angiogenesis assay, Matrigel
assay, and vessel densities) in diabetic mice.91 Furthermore, in
vitro treatment with ephrin-B2/Fc improves the adhesion and
migration of peripheral blood mononuclear cells, raises the
number of circulating vascular progenitor cells, and enhances
their proangiogenic potential in the diabetic mouse model.92
Moreover, folic acid treatment also shows to normalize the
majority of the altered gene expression profiles of EPCs from
patients with type 1 DM compared with healthy subjects.93
In the diabetic mouse model, the overexpression of eNOS in
EPCs improves their proangiogenic and antiatherogenic properties.94 Interestingly, recent studies have suggested that hydrogen sulfide has proangiogenic effects, which improve wound
healing via the restoration of EPC functions in diabetic mice.95
Similarly, direct administration of cytokines or a gene vector encoding those cytokines, such as SDF-1α56 and VEGF,96
or a cocktail of these cytokines derived from cultured EPCs
of healthy pluripotent cell lines, such as human embryonic
stem cells,97 can reverse EPC dysfunction in patients with DM.
Although the number of EPCs in patients with DM did not correlate with the plasma level of adiponectin,19 treatment of EPCs
with adiponectin prevented their senescence induced by hyperglycemia.50 Because downregulation64,65 of microRNA can contribute to EPC dysfunction in DM, microRNA-based treatment
to restore the expression of microRNA 126 and microRNA
130a may be a potential novel therapeutic approach.
Finally, a direct delivery of EPCs isolated from BM to the
injured/ischemia tissue may reverse the trafficking and homing defects induced by DM. Nevertheless, the proliferative and
angiogenic capacity of exogenous EPCs is impaired in DM. An
exogenous source of EPCs such as those derived from pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem cells, can avoid this issue.13 Nonetheless, other
issues related to the use of such cell sources, such as risk of
immune rejection and tumor formation, need to be addressed.
Future Perspectives
Although an association between endothelial dysfunction and
vascular complications in DM is well established, emerging data
from experimental and clinical studies suggest that alterations of
EPCs may play a pivotal role in the development of microvascular and macrovascular complications. Current therapies that aim
to control hyperglycemia, dyslipidemia, and hypertension have
been shown to improve EPC number and function in patients
with DM. It is unclear whether these improvements are simply a
result of the control of these conventional risk factors or independent effects. More importantly, whether the additional pleiotropic
effect of these agents on EPCs can further prevent microvascular
Yiu and Tse Diabetes Mellitus and Endothelial Progenitor Cells 1141
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and macrovascular complications in DM is also unknown. For
example, thiazolidinediones seem to provide better improvement
in EPCs compared with metformin, yet they fail to demonstrate
any benefit on clinical outcomes in patients with DM.98 It is possible that existing methods used to determine EPCs are misleading. Indeed, EPCs are a heterogeneous population of progenitor
cells with different stages of differentiation, and their surface
marker profiles change throughout their lifespan.10 Furthermore,
EPCs possess different phenotypes including a proinflammatory
(harmful) or angiogenic (protective) capacity, depending on their
surrounding environment.99 Therefore, the balance between the
proportions of EPCs with these different phenotypes may play an
important role in the pathogenesis of vascular diseases.
For the assessment of EPCs, the enumeration of EPCs based
on their phenotypes, that is, early versus late EPCs as well as
their in vitro and in vivo functional capacity, should be a preferable surrogate marker compared with simple measurement of
EPCs as defined by the expression of surface markers. However,
further standardization of cell isolation methods and culture protocols is urgently needed to allow future comparison between
different studies. Moreover, future studies are needed to compare the uses of different agents and approaches, alone and in
combination, as optimal therapeutic approaches to improve EPC
function and thus clinical outcome in patients with DM.
Sources of Funding
This work was supported by the Philip KH Wong Foundation for
Cardiovascular Stem Cell Research, Sun Chieh Yeh Heart Foundation,
and Research Grant Council of Hong Kong’s Theme Based Research
Scheme (T12-705/11).
Disclosures
None.
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Significance
Diabetes mellitus and its associated cardiovascular complications represent major health threats. This review summarizes the recent understandings on the pathophysiological role of circulating exogenous endothelial progenitor cells on the occurrence and severity of microvascular and macrovascular complications, as well as the potential novel therapeutic approaches to prevent and treat diabetes mellitus–related
cardiovascular complications via the restoration of endothelial progenitor cell number and function in diabetes mellitus.
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Specific Role of Impaired Glucose Metabolism and Diabetes Mellitus in Endothelial
Progenitor Cell Characteristics and Function
Kai-Hang Yiu and Hung-Fat Tse
Arterioscler Thromb Vasc Biol. 2014;34:1136-1143; originally published online April 17, 2014;
doi: 10.1161/ATVBAHA.114.302192
Arteriosclerosis, Thrombosis, and Vascular Biology is published by the American Heart Association, 7272
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Supplemental Table I: Clinical studies reporting endothelial progenitor cells (EPCs) alteration in patients with
diabetes mellitus
Study
Patients
Type 1 Diabetes Mellitus
Loomans et al
T1DM n=20,
1
(2004)
Control: n=20
Asnaghi V, et al.
(2006)2
Sibal et al. (2009)3
T1DM with
(n=11) or without
(n=12) DR
Control n=11
T1DM n=74
Control n=80
Brunner S, et al.
(2009).4
T1DM with
(n=60) or without
(n=30) DR
Dessapt et al.
(2010)5
T1DM with
(n=22) or without
(n=22)
microalbuminuria
Finding
Interpretation
Reduced cultured early EPCs
(characterized by uptake of DiI-labeled
adLDL, the binding of lectin UEA-1 and
CD31+) in T1DM patients and inversely
related with HbA1c.
Cultured EPCs as assessed by colony
forming units was higher in T1DM
patients with proliferative DR.
Patients with T1DM had reduced EPCs
and correlated closely with diabetic
control.
CD34/VE-cadherin+, CD133/VEcadherin+ and CD133/VEGFR-2+ EPC
counts were significantly lower in T1DM
patients, and significantly correlated with
brachial artery FMD.
CD34/CD133/CD309 EPCs was
reduced in nonproliferative retinopathy
but unchanged in proliferative DR
compared with those without DR.
However, CD34/CD133/CD309/CD31
mature EPCs was increased in
proliferative DR as compared with those
without DR.
Patients with microalbuminuria had
lower circulating CD34+ and
CD34/CD133+ EPCs and numbers of
colony-forming unit, and impaired
vascular endothelial growth factor
mediated tube formation.
Low EPC counts confirm risk of
macrovascular complications and may
account for impaired endothelial function
in T1DM patients
Increased clonogenic potential of EPCs in
T1DM patients with diabetic retinopathy.
In T1DM with DR, EPCs undergo stagerelated regulation. In non-proliferative
retinopathy, a reduction of EPCs was
observed, and in proliferative DR, a
dramatic increase of mature EPCs was
observed
Circulating EPC number is reduced and
function is impaired in T1DM patients with
microvascular injury as reflected by the
presence microalbuminuria.
Palombo et al.
(2011)6
T1DM n=16,
Control n=26
Reinhard H, et al
(2011)7
T1DM with
(n=37) or without
(n=35) diabetic
nephropathy
*Hörtenhuber et al. T1DM n=190,
(2013)8
Control n=34
GłowińskaOlszewska et al
(2013).9
T1DM n=52,
Control n=36
CD34/KDR+ EPC was lower in T1DM
patients than control and independently
associated with carotid intima media
thickness.
Cultured EPCs numbers were similar
between asymptomatic CVD T1DM
patients with or without diabetic
nephropathy.
CD34/CD133/KDR+ EPCs was reduced
in T1DM patients and correlated with
HbA1c. EPC count was associated with
glycemic control at 1 year of follow-up.
CD34/VE-cadherin+ and
CD34/VEGFR+ EPCs were higher in
children with T1DM that inversely
correlated with FMD.
Young subjects with T1DM had lower
EPCs that may contribute to subclinical
carotid atherosclerosis.
Cultured EPCs in T2DM patients had
decreased proliferation and impaired
tubule formation in Matrigel assay
compared with controls.
CD34/KDR+ EPCs is reduced in
patients with T2DM. T2DM patients with
PVD had reduced CD34+ EPCs.
EPCs in T2 DM patients exhibit
alterations in functions important for blood
vessel growth
Asymptomatic patients with diabetic
nephropathy had EPC numbers similar to
normoalbuminuric patients
Optimization of glycemic control in T1DM
patients may reduce cardiovascular
burden by increasing circulating EPCs.
Children with T1DM had higher circulating
EPCs that negatively correlated with
endothelial function.
Type 2 Diabetes Mellitus
Tepper et al
(2002)10
T2DM n=20
Control n=20
Fadini et al
(2005).11
T2DM n=51,
Control n=17
*Pistrosch F et al.
(2005).12
T2DM n=10
Control N=10
Number and migratory function of EPCs
were reduced in T2DM patients which
improved with after treatment with
rosiglitazone.
Patients with T2DM, in particular to those
with PVD, had reduced EPCs.
The finding suggested that depletion of
EPCs may contribute to the pathogenesis
of PVD.
PPARgamma-agonist rosiglitazone
increases number and migratory activity
of cultured EPCs in T2DM patients.
*Bahlmann FH, et
al (2005).13
T2DM n=38
Fadini et al
(2006).14
T2DM with
(n=72) or without
PVD (n=55)
Wang CH, et al.
(2006)15
T2DM n=36
Fadini et al
(2007).16
Middle-aged
individuals n=219
*Sorrentino SA, et
al. (2007)17
T2DM n=30
Control n=10
Egan et al
(2008).18
T2DM n=98,
Control n=39
CD34+ EPCs increased after treatment
with olmesartan (n=18) or irbesartan
(n=20) in T2DM patients
CD34/KDR+, CD34+, CD133+ EPCs
were reduced in T2DM patients with
PVD compared with those without PVD,
and EPC levels were negatively
correlated with the severity of PVD. The
clonogenic and adhesion capacity of
cultured EPCs were also significantly
lower in T2DM patients with PVD.
CD34/KDR+ EPCs level, migratory
response and the adhesive capacity
increased after 8 weeks of pioglitazone
CD34+ and CD34+/KDR+ EPCs were
reduced in those with T2DM and were
negatively correlated with glucose
tolerance.
Impaired in-vivo reendothelialization of
wire-induced carotid artery injured by
diabetic EPCs. EPCs from diabetic
individuals had a substantially increased
superoxide production and impaired NO
bioavailability. Rosiglitazone therapy
normalized NAD(P)H oxidase activity,
restored NO bioavailability, and
improved in vivo reendothelialization
capacity of EPCs from diabetic patients
T2DM patients had reduced
CD34/KDR+ and KDR+ EPCs levels.
Putative KDR+ EPCs were further
reduced in T2DM patients with
cardiovascular and microvascular
Angiotensin II receptor antagonists
increase the number of EPCs T2DM
patients
EPC decrease in T2DM patients was
related to PVD severity and that EPC
function was altered in those patients
with PVD
Pioglitazone increased the number and
improved the functional properties of
EPCs in T2DM patients
EPCs were negatively associated with
glucose tolerance and maybe a cause of
high incidence of cardiovascular damage
in patients with pre-diabetes.
In vivo reendothelialization capacity of
EPCs derived from T2DM patients was
severely impaired partially related to
increased NAD(P)H oxidase-dependent
superoxide production and subsequently
reduced NO bioavailability which can be
reversed by rosiglitazone.
T2DM patients had reduced EPCs which
was negatively associated with severity of
DM related complications.
*Makino J, et al.
(2008).19
Wong et al
(2008).20
T2DM n=34
Chen et al
(2009).21
T2DM n=51,
Non-diabetic
n=23
Makino H, et al.
(2009)22
T2DM n=85
Tan K, et al.
(2010)23
T2DM n=23
Control n=22
*Jaumdally RJ, et
al. (2010)24
CVD patients
with (n=14) or
without (n=10)
T2DM
Subjects with
different degree
of impaired
Fadini GP, et al
(2010).25
T2DM n=88
Control n=91
complication.
CD34+EPC significantly increased after
24 weeks of pioglitazone
T2DM patients had lower CD133/KDR+
and CD34/KDR+ EPCs levels, and
FMD, which were positively correlated
with daily thiamine intake.
The number of CD34+/KDR+ and
CD133/KDR+ EPCs levels were similar
between patients with T2DM and
controls. The migratory function of
cultured EPCs was impaired in T2DM
patients with and without critical leg
ischemia and non-diabetic patients with
critical leg ischemia compared with
control.
CD34+ EPCs negatively correlated with
urinary albumin excretion rate and
T2DM patients with lower EPCs had
increased urinary albumin excretion
after 12 months follow-up.
CD34+/CD45-EPCs were increased in
T2DM patients with proliferative DR, but
their migratory function was impaired.
80mg atorvastatin increased
CD34/CD133+ EPCs and angiopoietin2, decreased VEGF in T2DM patients.
Biphasic distribution on the level of
CD34+ cells with significantly reduced in
impaired glucose tolerance and in newly
Pioglitazone therapy increased CD34+
EPCs in T2DM patients
Reduced EPCs and FMD in T2DM
patients was related to a reduced daily
intake of thiamine.
The migratory function of EPCs was
impaired in T2DM patients even in those
without critical leg ischemia, suggesting
impaired migratory function of EPCs may
contribute to impaired neovascularization
and critical limb ischemia in T2DM
patients.
Decreased number of circulating EPCs
may be involved in the progression of
diabetic nephropathy
EPCs from T2DM patients with
proliferative DR are mobilized into the
circulation but may be unable to migrate
and repair damaged capillary
endothelium.
High-dose atorvastatin increased
circulating EPCs, reduced VEGF and
increased Ang-2 in T2DM patients with
CVD
Reduction of circulating EPCs occurred
after the onset of T2DM and progression
of diseases
Churdchomjan W,
et al. (2010)26
*Reinhard H, et al
(2010).27
*Fadini GP, et al.
(2010).28
Brunner S, et al.
(2011).29
Li M, et al,
(2011)30
Yue et al. (2011)31
glucose tolerance diagnosed T2DM and then decreased
n=425
further after 20 years of diabetes
compared with control.
T2DM n=36
CD34/VEGFR2+ EPCs count was
Control n=20
decreased in T2DM patients compared
with controls and there was an inverse
correlation between the EPC numbers
with plasma glucose and HbA1C. The
number and function of EPCs in patients
with good glycemic control were
recovered compared with those with
poor glycemic control.
T2DM n=28
Culture EPCs count increased by 35%
after 90 days of multifactorial
(metformin, aspirin, statin and
angiotensin II receptor blocker)
treatment
T2DM n=32
4 weeks treatment of sitagliptin
significant increased EPCs and SDF1alpha and decreased monocyte
chemoattractant protein-1 in T2DM
patients
T2DM with
CD34/CD133+, CD34/CD133/CD30+,
(n=66) or without and CD34/CD133/CD309/CD31+ EPCs
(n=60) CVD
were stepwise reduced in CVD T2DM
patients with increased severity of DR.
T2DM n=95
CD133+ and CD133/KDR+ EPCs were
Control n=95
independently associated with the
presence of T2DM, and the levels of
CD34+ and CD34/KDR+ EPCs were
independently associated with Hba1c.
T2DM n=234,
T2DM patients had reduced
Control n=121
CD34/KDR+ and CD133/KDR+ EPCs.
EPC dysfunction in T2DM might be partly
improved by strict glycemic control.
Numbers of EPC derived from peripheral
blood mononuclear cells increased
significantly after multifactorial
intervention in T2DM patients.
Sitagliptin increases circulating EPCs in
T2DM patients with concomitant
upregulation of SDF-1alpha.
T2DM patients with CVD showed a strong
retinopathy-stage-dependent depletion of
all angiopoietic EPCs.
Different subtype of circulating EPCs
were associated with T2DM and
hyperglycemia
EPCs and arterial stiffness were closely
related to glycemic control in patients with
Both EPCs subtype independently
T2DM.
associated with brachial-ankle pulse
wave velocity and HbA1c.
Yiu YF et al
T2DM n=280,
Patients with T2DM had reduced
Vitamin D deficiency might contribute to
(2011).32
Control n=73
CD133/KDR+ EPCs and correlated with depletion of immature EPCs and
vitamin D deficiency and impaired
endothelial dysfunction in T2DM patients.
brachial FMD.
Van Ark J, et al.
T2DM with
CD34+ and CD34/KDR+ EPCs were
Disturbed ratio between EPCs and
(2012).33
(n=35) or without reduced in T2DM patients. Culture
smooth muscle progenitor cells might
(n=16) CVD
EPCs was reduced in T2DM patients
contribute to CVD in T2DM patients.
Non-T2DM with
with CVD compared with those without
(n=36) or without CVD. However, there was no difference
(n=19) CVD
in circulating smooth muscle progenitor
cells.
Moon JH, et al
T2DM without
CD34/CD133/CD309+ EPCs were lower Reduced EPC count in T2DM patients
34
(2012).
CVD n=73
in T2DM patients with carotid artery
was associated with carotid
plaques, and lower EPC counts
atherosclerotic plaque formation in T2DM
independently correlated with carotid
patients
artery plaque formation.
Zhao CT, et al.
T2DM n=87
T2DM patients (n=34) with impaired
Myocardial dysfunction in T2DM patients
35
(2012)
myocardial function as determined strain was related to depletion of EPCs.
imaging had lower number of CD34+
EPCs than those with normal
myocardial function (n=53).
Abbreviations: CVD=cardiovascular diseases; DR=diabetic retinopathy; EPC= endothelial progenitor cells; FMD=flowmediated dilatation; NO= nitric oxide; PVD=peripheral vascular disease; T1DM= type 1 diabetes mellitus; T2DM= type 2
diabetes mellitus.
* Studies on therapeutic agents on EPC
Supplemental Table II. Studies reporting alteration and therapeutic effects of EPCs alteration in diabetic animal
model.
Study
Awad O, et al
(2006)36
Ii m, et al.
(2006)37
Fadini et al
(2006).38
Ohshima M, et
al. (2009)39
Kang L, et al
Animal model
Hindlimb ischemic
model in STZinduced diabetic
mice
Wire-induced
carotid denudation
in db/db mice
Hindlimb ischemiareperfusion injury
model in STZ
induced diabetic
rats
db/db mice
Hindlimb ischemic
Finding
CD34+ EPCs or CD14+ monocytic
progenitor cells derived from
peripheral blood improved healing and
vascular growth after limb ischemia.
Diabetic EPCs exhibited decreased
migration and adhesion activities in
vitro. Vascular endothelial growth
factor and endothelial NO synthase
expressions were reduced but
thrombospondin-1 mRNA expression
was significantly upregulated in
diabetic EPCs. Reendothelialization of
the injured artery was impaired by
malfunctioning EPCs in diabetes.
EPCs were unable to be mobilized in
diabetic rats compared to control.
Insulin, G-CSF and SDF-1α partially
restored the mobilization of EPCs in
diabetic rats.
Diabetic mice had reduced Flk1/CD34+ EPCs and higher
intracellular ROS levels, with lower
potency of endothelial differentiation
compared with control. Superoxide
dismutase-mimic decreased the
intracellular ROS level and increased
number and potency of differentiation
of EPCs.
Diabetic mice had reduced circulating
Interpretation
CD14+ cells could provide an alternative
therapeutic option for people with diabetes
when their CD34+ EPC number and
function are compromised.
Change in expression of thrombospondin-1
in diabetic EPCs might contribute to the
impaired reendothlialization after arterial
injury.
Administration of G-CSF and SDF-1, and
blood glucose control with insulin might
offer a therapeutic strategy for diabetic
ischemic syndromes via improving
mobilization of EPCs.
Antioxidant therapy attenuated the
diabetes-related impairment of EPCs
reducing oxidative stress
Impairment of ischemia-induced EPC
(2009)40
Olkawa et al
(2010).41
Albiero et al
(2011). 42
Kuliszewski et
al (2013).43
model in STZinduced diabetic
mice
EPCs and increased plasma
endothelial microparticles. Following
hindlimb ischemia, diabetic mice
exhibited suppressed EPC
mobilization, a reduction in the
expected increase in capillary density
and suppressed restoration of
transcutaneous oxygen pressure in
the ischemic tissue.
STZ-induced
Alteration of the bone marrow
diabetic mice
structure with depletion of
hematopoetic component and fatty
degeneration in mice with T1DM.
Cultured endothelial cells from T1DM
mice showed impaired migratory
function, network formation and
adhesiveness to BM mononuclear
cells.
Hindlimb skin
BM derived EPCs were reduced,
wound in STZincreased apoptosis and decreased
induced diabetic
proliferation in granulation tissue of
mice
diabetic mice compared with control
mice.
Lean Zucker, obese Circulating EPCs were reduced in
Zucker (model of
both MS and DM rats.
metabolic
Cultured EPCs from mice MS model
syndrome [MS])
had reduced EPCs differentiation,
and Zucker diabetic greater apoptosis, reduced migratory
fatty rats
response and matrigel tubule
formation, similar in diabetic model.
Both obese Zucker and Zucker
diabetic fatty rats had reduced EPCs
recruitment in the ischemic hindlimb
mobilization in the diabetic mouse model.
The study suggested that microangiopathy
was presence in the bone marrow of
diabetic mice.
Diabetes delayed wound healing in
association with defective recruitment,
survival and proliferation of BM derived
EPCs.
EPCs were reduced with functional
impairment in both diabetic and MS model.
model.
Westerweel
STZ-induced
In diabetic mice, bone marrow EPC
Diabetes induces alterations in the
PE, et al
diabetic mice
levels were unaffected, but the
progenitor cell supportive capacity of the
44
(2013)
circulating EPC levels in blood were
bone marrow stroma, which could be
lower at baseline and mobilization with partially responsible for the attenuated EPC
G-CSF/SCF was attenuated.
mobilization and reduced EPC levels.
Abbreviations as in Table I; G-CSF=granulocyte-colony stimulating factor; ROS=reactive oxidative species; SDF-1α =stromal cell-derived factor 1α; STZ=streptozotocin.
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