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H Y P E R T E N S I O N

Endothelial Dysfunction in Diabetes


The role of reparatory mechanisms
ANGELO AVOGARO, MD, PHD SAULA DE KREUTZENBERG, MD, PHD the M3 subtype of muscarinic receptors in
MATTIA ALBIERO, PHD GIAN PAOLO FADINI, MD coronary arteries when endothelial integ-
LISA MENEGAZZO, PHD rity is lost. This response suggests that
endothelial cells exposed to hyperglyce-
mia face an apoptotic process, leading to
intimal denudation. The apoptotic pro-

T
ype 2 diabetes is characterized by a of endothelium-derived hyperpolarizing cess takes place through a complex series
two- to fourfold increased risk of factor predominates in smaller resistance of events: the b1-integrin signaling path-
cardiovascular disease. This is gen- vessels. way is an initiator/sensor for apoptosis
erally attributed to the adverse effects of In patients with diabetes, endothelial induced by mechanical stretch: after in-
hyperglycemia and oxidative stress on dysfunction appears to be a consistent tegrin activation, mechanical stretch in-
vascular biology. It has also been shown nding; indeed, there is general agree- duces increased p38 mitogenactivated
that patients with prediabetic conditions, ment that hyperglycemia and diabetes protein kinase (MAPK) and c-Jun N-
such as impaired fasting glucose and im- lead to an impairment of NO production terminal protein kinase (JNK) activation
paired glucose tolerance, are at increased and activity. The endothelium has a lim- leading to cell apoptosis. In endothelial
risk of cardiovascular disease as well (1). ited intrinsic capacity of self-repair, being cells, disturbed ow stress results in en-
This result suggests that abnormalities in built up by terminally differentiated cells doplasmic reticulum (ER) stress response
carbohydrate metabolism form a contin- with a low proliferative potential. That is and to vascular endothelial-cadherin sup-
uum that progressively worsens cardio- why endothelial repair is accomplished pression (5). The downregulation of vas-
vascular health; the rst step of the through the contribution of circulating cular endothelial-cadherin activates the
adverse sequence of events that leads to cells, namely endothelial progenitor cells caspase protein family, resulting in endo-
the atherosclerotic process is thought to (EPCs), in physiological and pathological thelial apoptosis that takes place mainly at
be endothelial dysfunction (2). conditions. In this review, we will outline atherosusceptible arterial sites. The con-
Vascular endothelial cells play a ma- the mechanisms of endothelial dysfunc- sequence of the apoptotic process is de-
jor role in maintaining cardiovascular tion in diabetes, the role of EPCs in tachment of endothelial cells, which are
homeostasis. In addition to providing a cardiovascular homeostasis, and the im- released into the bloodstream and can be
physical barrier between the vessel wall plications of EPC alterations in diabetes recognized and measured as circulating
and lumen, the endothelium secretes a and its complications (Fig. 1) (3). endothelial cells. In some circumstances,
number of mediators that regulate platelet endothelial cells do not detach as entire
aggregation, coagulation, brinolysis, and BIOLOGY OF ENDOTHELIAL cells, but as apoptotic endothelial micro-
vascular tone. The term endothelial dys- DYSFUNCTION AND particles. McClung et al. (6) have shown
function refers to a condition in which REGENERATION IN that circulating endothelial cell levels are
the endothelium loses its physiological DIABETESIt is accepted that gener- higher in type 2 diabetic patients, irrespec-
properties: the tendency to promote vaso- alized endothelial dysfunction precedes tive of glucose control, represented by
dilation, brinolysis, and anti-aggregation. the development of atherosclerosis. HbA1c levels. Besides circulating endothe-
Endothelial cells secrete several mediators When endothelium is exposed to hy- lial cells, microparticles (endothelial micro-
that can alternatively mediate either vaso- perglycemia, an array of negative intra- particles) released from intact cells may
constriction, such as endothelin-1 and cellular events promotes endothelial also play a role in the normal hemostatic
thromboxane A2, or vasodilation, such dysfunction. In diabetic patients, the re- response, since they have a powerful
as nitric oxide (NO), prostacyclin, and sponse of coronary circulation exposed to procoagulant activity. Elevated endothelial
endothelium-derived hyperpolarizing increasing amounts of acetylcholine is a cellderived endothelial microparticle
factor. NO is the major contributor to paradoxical constriction instead of vaso- levels are predictive of the presence of cor-
endothelium-dependent relaxation in dilation (4). Contraction instead of vaso- onary artery lesions, and it is a more signif-
conduit arteries, whereas the contribution dilation induced by ACh is mediated via icant independent risk factor than duration
of diabetes, lipid levels, or presence of
c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c
hypertension (7). The consequence of the
From the Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy, and the apoptotic process is the so-called arterial
Medical School, Padova, Italy. denudation, which triggers important pro-
Corresponding author: Angelo Avogaro, angelo.avogaro@unipd.it.
This publication is based on the presentations at the 3rd World Congress on Controversies to Consensus in atherosclerotic processes such as smooth
Diabetes, Obesity and Hypertension (CODHy). The Congress and the publication of this supplement were muscle cell proliferation, migration, and
made possible in part by unrestricted educational grants from AstraZeneca, Boehringer Ingelheim, Bristol- matrix secretion. For this reason, endothe-
Myers Squibb, Daiichi Sankyo, Eli Lilly, Ethicon Endo-Surgery, Generex Biotechnology, F. Hoffmann-La lial reparatory mechanisms are fundamen-
Roche, Janssen-Cilag, Johnson & Johnson, Novo Nordisk, Medtronic, and Pzer.
DOI: 10.2337/dc11-s239
tal in reestablishing vessel integrity.
2011 by the American Diabetes Association. Readers may use this article as long as the work is properly
cited, the use is educational and not for prot, and the work is not altered. See http://creativecommons.org/ EPCsEPCs are immature cells capable
licenses/by-nc-nd/3.0/ for details. of differentiating into mature endothelial

care.diabetesjournals.org DIABETES CARE, VOLUME 34, SUPPLEMENT 2, MAY 2011 S285


Endothelium reparation

homing of circulating CXCR4+ stem cells,


reduced cardiac remodeling, and improved
heart function and survival. We recently
conrmed the effect of DPP-4 inhibition
on EPCs in vivo in type 2 diabetic patients.
After 4 weeks, patients receiving the
DPP-4 inhibitor sitagliptin, compared
with control subjects, showed a signicant
increase of EPCs and SDF-1a and a de-
crease in MCP-1 (12).
To heal a damaged endothelium,
EPCs themselves are required to trans-
migrate (extravasation) to promote new
vessel growth; the rolling phase of extrav-
asation is mediated by E- and P-selectins.
Subsequent rm attachment is mediated
via intercellular adhesion molecule-1/
leukocyte functionassociated antigen-1,
vascular cell adhesion molecule-1/very
late antigen (VLA)-4 ligand pairs, and
junctional adhesion molecules. Integrins
Figure 1Schematic biological role of endothelial progenitor cells, their role in diabetes, and
potentially available treatment aiming to restore their circulating concentration. See text for mediate the adhesion and transmigration
further explanations. Ox, oxidative. of stem and progenitor cells. In particular,
b2-integrins are essential for homing and
improvement of neovascularization me-
cells. Vascular injury and tissue ischemia, involved in the angiogenic response, and diated by EPCs after hind limb ischemia
through the release of growth factors and erythropoietin (9). Then, growth factors in mice. Transendothelial migration of
cytokines, mobilize EPCs, which, once in allow bone marrow EPCs to undergo cells requires degradation of basement
the peripheral circulation, specically transendothelial migration and to pass membrane, which depends on the pro-
home in on the ischemic sites to stimulate into the peripheral blood by means of at- duction of matrix-degrading enzymes, es-
compensatory angiogenesis. Moreover, tenuating stromal cellstem cell interac- pecially those capable of degrading type IV
EPCs constitute a circulating pool of cells tions and by rearranging extracellular collagen, such as matrix metalloproteinases
able to form a cellular patch at sites of matrix. EPC mobilization is characterized (MMPs). MMP-2 and MMP-9 are known to
endothelial injury, thus contributing di- by both a loss in cell-cell contacts and a be expressed by all cell types that migrate
rectly to the homeostasis and repair of the desensitization of chemokine signaling, through the endothelial cell layer, includ-
endothelial layer. EPCs have now been notably the SDF-1a/C-X-C chemokine re- ing leukocytes, tumor cells, and hemato-
recognized as playing a major role in ceptor 4 (CXCR4) axis, the fundamental poietic stem cells (13).
cardiovascular biology: in fact, the extent signaling pathway underlying stem cell
of the circulating EPC pool is now mobilization and homing during tissue
considered a mirror of cardiovascular homeostasis and injury (10). On the con- EPC ALTERATIONS IN
health (8). Virtually all risk factors for ath- trary, stem cell homing requires upregula- DIABETESBoth type 1 and type 2
erosclerosis have been associated with de- tion of cell adhesion molecules and diabetic patients have less circulating
crease and/or dysfunction of circulating activation of the SDF-1a/CXCR4 axis. EPCs than matched healthy subjects (3).
EPCs, whereas an expanded EPC pool is The majority of cytokines that mediate We have recently shown that CD34+ pro-
associated with a decreased cardiovascu- stem cell migration do so via modulation genitor cell reduction marks the clinical
lar mortality. either of SDF-1a or of its receptor, CXCR4. onset of type 2 diabetes and that defective
Denition of the antigenic phenotype Under homeostatic conditions, most pro- mobilization appears to be the most likely
of EPCs in accordance with the term en- genitors remain in the bone marrow mechanism involved. We have also
dothelial progenitors should include at compartment, retained by high SDF-1a shown that a partial recovery of progeni-
least one marker of immaturity/stemness expression, which is maintained by the tor cell level occurs during the subsequent
(for instance, CD34 or CD133) plus at hypoxic microenvironment. After an is- 1020 years, but bone marrow reserve
least one marker of the endothelial line- chemic insult, soluble factors, such as seems exhausted in the long term (14).
age. Tissue ischemia is considered the SDF-1a, are released by injured tissue Diabetic EPCs also display functional im-
strongest stimulus for EPC mobilization, and stimulate mobilization of progenitor pairment, such as reduced proliferation,
through the activation of hypoxia-sensing cells from the bone marrow. These cells adhesion, migration, and incorporation
systems, such as hypoxia inducible factor are recruited to ischemic tissue by high into tubular structures (15). The mech-
(HIF)-1a (3). The resulting active HIF-1a local levels of SDF-1a, providing a per- anisms underlying EPC reduction in
binds to enhancer DNA regions and pro- missive niche. Interestingly, SDF-1a is diabetes include weak bone marrow mo-
motes the transcription of oxygen-sensible cleaved and inactivated by CD26/dipep- bilization, decreased proliferation, and
genes encoding, among others, vascular tidyl peptidase 4 (DPP-4). Zaruba et al. shortened survival. Recently, Sambuceti
endothelial growth factor (VEGF), stromal (11) showed that the pharmacological in- et al. (16) experimentally showed that
derived factor-1a (SDF-1a), other genes hibition of DPP-4 increased myocardial type 2 diabetes and its related oxidative

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Avogaro and Associates

stress hamper the interaction between the normal EPC pool. These observations stimulate vascularization, even becoming
vascular wall and normal EPCs by mech- may provide a possible explanation for anti-angiogenic. We have shown that non-
anisms that are, at least partially, reversed the delayed post-ischemic vascular heal- diabetic patients with peripheral arterial
by induction of HO-1 gene expression, ing and myocardial recovery in diabetes. disease alone and in patients with uncom-
adiponectin, and pAMPK levels. Despite the evidence that high glucose plicated diabetes had similar EPC reduc-
The expression of angiogenic factors can induce EPC apoptosis in culture, tion versus control subjects (24). Patients
VEGF and HIF-1a are reduced in the there are no robust data suggesting that with diabetes and peripheral arterial dis-
hearts of diabetic patients during acute hyperglycemia is associated with in- ease had a further signicant decrease in
coronary syndromes, and myocardial in- creased progenitor cell apoptosis in vivo. circulating EPC levels, especially in the
farct size in the rat is increased because Indeed, we found a certain inverse corre- presence of ischemic foot lesions. Remark-
of a reduced expression of HIF-1a; there- lation between peripheral blood CD34+ ably, EPC levels strongly correlated with
fore, poor collateral formation in diabetes cell level and percentage of apoptotic the ankle-brachial index, the most objec-
may be attributed at least in part to weaker CD34+ cells, but there was no increase tive diagnostic and prognostic test for
bone marrow stimulation from the ischemic in the apoptotic rate of CD34+ cells in di- lower-extremity arterial disease. Diabetes
tissue. We have shown that bone mar- abetic patients with overt hyperglycemia also predisposes patients to heart failure.
row mobilization of EPCs after ischemia- compared with control subjects (14). Spectroscopic and histological evidence in
reperfusion injury is defective in diabetic Therefore, the mechanisms that reduce the human myocardium indicates a mal-
rats compared with nondiabetic rats (17). progenitor cell survival in the diabetic adaptive metabolic response in diabetes,
The inability to mobilize EPCs was associ- bloodstream need further investigation. characterized by intramyocellular triglyc-
ated with a downregulation of HIF-1a and Another possible link between diabetes eride accumulation. In diabetes, there is
weakened release of marrow-stimulating and EPC alterations is the effect of insulin also evidence for a link between myocar-
factors, such as VEGF and SDF-1a, ulti- resistance per se. We have shown that pa- dial actin isoform switching, calcium ho-
mately leading to insufcient compensa- tients with the metabolic syndrome have meostasis, and altered metabolism in the
tory angiogenesis after ischemia. HIF-1a decreased levels of CD34 + KDR + EPCs development of heart failure. In the dia-
deregulation in diabetes may be deter- compared with patients without the syn- betic heart, microvascular abnormalities
mined by an overproduction of reactive drome (21). Oxidative stress appears as a are also frequently present. There are
oxygen species (ROS): indeed, it was major determinant of long-term diabetes some experimental data indicating that
shown that ROS inhibition was able to complications. Two studies have recently EPC alterations are implicated in the path-
normalize post-ischemic neovasculariza- demonstrated that the natural transketo- ogenesis of diabetic cardiomyopathy as
tion in diabetes by positive EPC modula- lase activator, benfotiamine, which pre- well. Yoon et al. (25) have demonstrated
tion (18). We found that bone marrow vents the subcellular damage pathways that diabetic cardiomyopathy in rats is
EPC mobilization was partially rescued triggered by oxidative stress, restored characterized by an early and progressive
in diabetic rats treated with insulin, albeit EPC-mediated healing of ischemic diabetic decline in myocardial VEGF expression
it is not known whether this favorable ef- limbs in mice and prevented hyperglycemia- that reduces capillary density, increases -
fect was mediated by insulin itself or by an mediated EPC dysfunction, via modulation brosis, and impairs contractility. Cardiac
improved glucose control. Humpert et al. of the Akt pathway (22). Ceradini et al. (18) stem cell aging and heart failure associated
(19) showed that insulin therapy in de- found HIF-1a function is impaired in with diabetes can be prevented by deletion
compensated diabetic patients increased diabetes because of ROS-induced modi- of the stress-related gene p66Shc, which
CD34+CD133+ progenitor cell count, de- cation by the glyoxalase-1 substrate meth- we have shown to be potently upregulated
pending on SDF-1a polymorphism. ylglyoxal. Decreasing superoxide in diabetic in type 2 diabetic subjects (26). The dis-
Thus, it can be hypothesized that better mice corrects post-ischemic defects in neo- covery that alterations of circulating and/
metabolic control, in general and speci- vascularization, oxygen delivery, and che- or local progenitor cells may mediate this
cally during acute ischemic syndromes, mokine expression and normalized tissue complication could identify novel thera-
may induce a more efcient stimulation survival. In hypoxic EPCs cultured in high peutic strategies.
of EPC-mediated neovascularization in glucose, overexpression of GLO1 prevented Diabetes is one leading cause of
ischemic tissue, thus reducing residual is- reduced expression of both the SDF-1a re- chronic kidney disease. Endothelial dam-
chemia. We have also shown that diabetes ceptor CXCR4 and endothelial NO synthase, age and microcirculatory impairment are
is characterized by altered activation of an enzyme essential for EPC mobilization. early pathogenetic events in diabetic ne-
phosphatidylinositol (PI) 3-kinase/Akt path- phropathy and may partly depend on
ways and by reduced NO bioavailability. EPC AND DIABETES EPC defects (27). Moreover, it can be sug-
Dysfunction of these subcellular pathways COMPLICATIONSThe severity of gested that EPCs are pluripotent and re-
may be involved in the defective mobiliza- macrovascular complications in diabetes tain the ability to transdifferentiate into
tion of EPCs from bone marrow (17). has been attributed to an impaired collat- disparate phenotypes (28). Therefore, a
Hyperglycemia, through the produc- eralization of vascular ischemic beds, decline in EPCs may be one mechanism
tion of ROS, may directly affect EPCs. which is insufcient to overcome the of defective glomerular repair and renal
Krnkel et al. (20) demonstrated that high loss of blood ow and leads to critical disease progression in diabetes. A recent
glucose impairs proliferation, survival, limb ischemia that often requires ampu- study has demonstrated that type 2 dia-
and function of cultured EPCs, with con- tation. In animal models of diabetic vas- betic patients with low CD34+ cells have a
comitant decreased NO production and culopathy, defective collateralization higher albumin excretion rate compared
MMP-9 activity. A denite demonstration was counteracted by administration of with patients with a high CD34 + cell
is that correction of hyperglycemia by in- EPCs from control animals (23). Con- count (29). The relationship between
sulin therapy can indeed restore the versely, diabetic EPCs were not able to EPCs and microalbuminuria has also

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Endothelium reparation

been recently conrmed in type 1 diabetic is an early and selective event leading to circadian release of EPCs and a marked
patients (30). The relationship between endothelial activation and proliferation reduction in clock gene expression in the
renal function and EPCs are more complex, in the retina, and CD34+ progenitors of retina and in EPCs themselves.
because the kidney-derived hormone perivascular cells have been demon-
erythropoietin has emerged as one major strated in peripheral blood (36). Thus, ALL THAT GLITTERS IS NOT
regulator of EPC mobilization and differen- depletion of generic CD34+ progenitor GOLDEPCs were proposed as a re-
tiation (31). The oxygen-erythropoietin cells may be one cause of pericyte loss, generative tool for treating human vascu-
feedback, which depends on the hypoxia- whereas increased endothelial differ- lar disease. However, conicting results
sensing system HIF-1a, is dysregulated in entiation may lead to abnormal retinal have been reported in the identication,
diabetes: microangiopathy and progressive angiogenesis. characterization, and precise role of EPCs
tubulointerstitial brosis increase the Diabetic neuropathy is caused by in vascular biology. Indeed, the direct
latency of the erythropoietin system, while both imbalances in neuron metabolism proof-of-concept of true signicance of
production of ROS and hyperglycemia and impaired nerve blood ow. Mainte- these cells in vascular repair and growth is
itself affect HIF-1a regulation, blunting nance of an adequate supply of blood still under scrutiny. Vascular homeostasis
the erythropoietin response (32). In this through vasa nervorum is essential to and specically repair are complex mul-
context, we have shown that EPC mobili- prevent the development of neuropathy. ticellular processes that require several
zation in diabetes is defective because of EPCs could be important in the homeo- cellular phenotype-like endothelial cells,
HIF-1a downregulation (17). For these stasis of the nutritive microvasculture, smooth muscle cells, monocytes, and
reasons, diabetic nephropathy may be as- and their exhaustion or dysfunction bone marrowderived cells. Hagensen
sociated with a more profound EPC im- may accelerate the course of diabetic et al. (40) have also recently questioned
pairment than chronic kidney disease in neuropathy. Because uncommitted pro- the role of EPCs in vascular repair by
general that would represent an incremen- genitor cells derived from adult blood can showing that bone marrowderived cells
tal risk of cardiovascular disease and death. differentiate also toward the neural phe- rarely contribute to the endothelium
Hyperglycemia induces retinal ische- notype, it is possible that a broader de- of developing plaques or participate in
mia and release of angiogenic factors that rangement of immature circulating cells endothelial regeneration after plaque
stimulate the proliferation of microves- in diabetes predisposes to this chronic rupture. Using orthotropic arterial trans-
sels, leading to proliferative retinopathy. complication. Naruse et al. (37) showed plantation, the authors convincingly
Not only local endothelial cells but also that intramuscular administration of demonstrate that circulating cells rarely
bone marrowderived EPCs may be in- EPCs is able to reverse the impairment contribute to plaque endothelium or re-
volved in the development of proliferative of sciatic nerve conduction velocity and generation of overlying endothelium after
retinopathy. This scenario appears para- nerve blood ow in diabetic rats. Once plaque disruption. This set of studies in-
doxical, since in diabetic patients, vascu- more, the altered EPC regulation in dia- directly suggests that the local vessel is
lar ischemia may coexist with a condition betic neuropathy may be attributed to a the major source of plaque endothelium
of pathological neovascularization. With defective HIF-1a activation. Jeong et al. and predominantly contributes to regen-
this background, to explore this so-called (38) investigated whether diabetic neu- eration of overlying endothelium after
diabetic angiogenic paradox, we studied ropathy could be reversed by local trans- plaque rupture. All this is further compli-
in vivo the levels of generic CD34+ pro- plantation of EPCs. They found that cated by the lack of a specic marker and
genitors and CD34+KDR+ EPCs and in motor and sensory nerve conduction validated methods to unequivocally iden-
vitro differentiation of EPCs from type 2 velocities, blood ow, and capillary den- tify this circulating cell subset and by the
diabetic patients with various combi- sity were reduced in sciatic nerves of presence of platelet microparticles in a
nations of peripheral arterial disease streptozotocin-induced diabetic mice standard assay for putative EPCs (41). A
and diabetic retinopathy (33). Whereas but recovered to normal levels after rare population of endothelial colony-
CD34+KDR+ cells and endothelial differ- hind-limb injection of bone marrow forming cells has been identied in hu-
entiation of cultured progenitors were derived EPCs. Injected EPCs were prefer- man umbilical cord blood and adult
selectively reduced in peripheral arterial entially and durably engrafted in the peripheral blood that embodies all of the
disease patients, generic CD34+ progeni- sciatic nerves. Finally, they found that properties of an EPC (42); however, there
tors were reduced in diabetic retinopathy portions of engrafted EPCs were uniquely is no proof that the human endothelial
patients, which showed instead higher localized in close proximity to vasa nervo- colony-forming cells play a role in neo-
clonogenic potential and enhanced endo- rum. This study proves, for the rst time, angiogenesis in vivo.
thelial differentiation in culture. Similar that bone marrowderived EPCs could re-
ndings have been reported by Asnaghi verse various manifestations of diabetic CONCLUSIONSDespite some stim-
et al. (34), who showed that EPCs cul- neuropathy. Remarkably, it was recently ulating controversy regarding EPC identity
tured from peripheral blood of patients shown by Busik et al. (39), using a rat and function, the literature is remarkably
with type 1 diabetes and proliferative di- model of type 2 diabetes, that the decrease consistent in attributing to EPCs a central
abetic retinopathy displayed increased in EPC release from diabetic bone marrow role in the development and progression
clonogenic potential. It was recently is caused by bone marrow neuropathy and of virtually all diabetes complications.
shown by Brunner et al. (35) that in patients that these changes precede the develop- Therefore, ways to reverse EPC alterations
with type 1 diabetes with diabetic retinop- ment of diabetic retinopathy. Denervation in diabetic patients should be actively
athy, EPCs undergo stage-related regulation was accompanied by increased numbers of pursued. Available data suggest that met-
and may play an important role in the de- EPCs within the bone marrow but decreased abolic intervention by either lifestyle
velopment of human proliferative diabetic numbers in circulation. Furthermore, de- change or glucose lowering is able to
retinopathy. Interestingly, pericyte loss nervation was accompanied by a loss of improve EPC biology. In addition, many

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drugs commonly prescribed in diabetic inhibition and G-CSF improves cardiac of type 2 diabetes mellitus. J Am Coll Car-
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oral dipeptidyl peptidase-4 inhibitor si- lar endothelial growth factor expression
these ndings. In patients with advanced
tagliptin increases circulating endothelial is a seminal event in diabetic cardio-
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16071609 plenishment of local vascular endothelial
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interest relevant to this article were reported. oxide synthase for mobilization of stem 26. Rota M, LeCapitaine N, Hosoda T, et al.
and progenitor cells. Nat Med 2003;9: Diabetes promotes cardiac stem cell aging
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