Circulation Research. 2006;98:4-6
doi: 10.1161/01.RES.0000200396.90220.41
(Circulation Research. 2006;98:4.)
© 2006 American Heart Association, Inc.
Molecular Basis of Angiopathy in Diabetes Mellitus
Jean-Sébastien Silvestre,
Bernard I. Lévy
From the Centre for Cardiovascular Research Lariboisière; INSERM Unit 689, Paris, France.
Correspondence to Bernard I. Lévy, Centre for Cardiovascular Research Lariboisière; INSERM Unit 689, 41 Bd de la Chapelle, 75475 Paris Cedex 10, France. E-mail: levy{at}larib.inserm.fr
See related article, pages 5562
Key Words: diabetes Ischemia angiogenesis PDGF-BB
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Introduction
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Cardiovascular complications are the leading cause of morbidity
and mortality in patients with diabetes mellitus; up to 80%
of deaths in patients with diabetes are closely associated with
vascular disease. The ability of the organism to form a collateral
network of blood vessels constitutes an important response to
vascular occlusive disease and determines to a large part the
clinical consequences and severity of tissue ischemia. The development
of new vessels is significantly reduced in diabetic patients
with coronary or peripheral artery disease.
1,2 This probably
contributes to the severe course of limb ischemia in diabetic
patients, in which peripheral artery disease often results in
foot ulceration and lower extremity amputation.
Diabetic retinopathy remains one of the major causes of acquired blindness in developed nations. This is true despite the development of laser treatment, which can prevent blindness in the majority of those who develop macular edema or proliferative diabetic retinopathy. The hallmark of diabetic retinopathy is the lack of microvessels in the macula, leading to hypoxia, associated with peripheral retinal neovascularization that may ultimately cause severe vitreous cavity bleeding and/or retinal detachment. The factors that stimulate retinal blood vessel growth have not been fully defined, but there is accumulating evidence that the renin-angiotensin-bradykinin system (RAKS) may be involved in a number of retinal vascular disorders, including retinopathy of prematurity and proliferative diabetic retinopathy3,4
Only a few studies have specifically evaluated the effect of diabetes on angiogenesis in ischemic vascular disease and in the retina. Moreover, the mechanisms by which diabetes could both limit the formation of new blood vessels in most organs and simultaneously induce proliferative diabetic retinopathy remain largely undefined.
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Main Molecular Mechanisms of Ischemia-Induced Neovascularization
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After acute ischemia, hypoxia and inflammation are believed
to be the major stimuli causing neovascularization.
5 Cells exposed
to hypoxia respond by increasing the level of hypoxia-inducible
factor-1 (HIF-1). This factor then activates a number of genes
by binding to hypoxia response elements in their promoter regions.
A second hypoxia-responsive factor, HIF-2, can activate many
of the same genes as HIF-1, such as the vascular endothelial
growth factor (VEGF).
6 VEGF is a major proangiogenic factor
activating phosphatidylinositol-3'-kinase/Akt and thus the cell
survival, migration, and proliferation.
7 Akt has been shown
to phosphorylate endothelial nitric oxide synthase (eNOS) leading
to a persistent calcium-independent enzyme activation and enhanced
endothelial NO synthesis and thereby influences the long-term
regulation of vessel growth. A large body of literature indicates
an essential role of endothelial NO for postnatal neovascularization.
8 The downstream effector pathways, by which NO mediates its effects,
are less clear but may involve integrin-linked signal transduction
processes.
Inflammatory processes are also necessary in the ischemia-induced neovascularization process. Activated monocytes and macrophages have been evidenced in ischemic tissues; these cells adhere to the vascular wall during angiogenesis and activate the production of both proangiogenic cytokines such as basic fibroblast growth factor (bFGF), VEGF, IL-18 binding protein, tumor necrosis factor (TNF)-
, and matrix metalloproteinases (MMPs), a family of enzymes that proteolytically degrade various components of the extracellular matrix.912
Ischemia-induced neovascularization also involves circulating vascular progenitor stem cells. After tissue ischemia, progenitor endothelial cells are mobilized from the bone marrow to the blood stream, and then home to ischemic tissues where they promote neovascularization through the paracrine production of growth factors and possible also by incorporation into neovessels.1315
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Impaired Ischemia-Induced Neovascularization in Diabetes
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In diabetic patients, collateralization and angiogenesis are
insufficient to overcome the loss of blood flow through narrowed
or occluded arteries leading to ischemia and often nontraumatic
limb amputation. However, only few studies have focused on the
identification of factors that may affect neovascularization
in the setting of ischemia in diabetes. It has been suggested
that alteration in VEGF expression and signalization participate
to neovascularization abnormalities in diabetes mellitus.
2 Attenuation
of the ability of monocytes to migrate has also been reported
in diabetic patients because of a downstream signal transduction
defect. The abrogation of the resulting inflammatory reaction
might be critical to the formation of new blood vessels in this
context.
16 Increased formation of advanced glycation end-products
(AGEs) is also regarded as one of the main mechanisms responsible
for vascular damage in patients with diabetes. Glycation of
extracellular matrix is a consequence of prolonged elevated
glucose levels that react with proteins by a nonenzymatic posttranslational
modification process called nonenzymatic glycation. This process
is purely adventitious and therefore is likely to be more important
in proteins possessing a long biological half-life such as collagen.
17 In experimental models of diabetes, the ability to inhibit these
pathways prevented diabetic retinopathy.
18 AGE formation has
also been shown to reduce the proteolysis of the glycated proteins
and therefore may affect the angiogenic reaction. Hence, pharmacological
inhibition of AGE formation is able to restore the ischemia-induced
revascularization process in mice hindlimb.
19 Finally, reduction
in the mobilization, differentiation, and incorporation of endothelial
progenitor cells at the level of the neo-vessels might participate
to the angiogenic deficit in a diabetic context. In a diabetic
type-1 mouse model, it has been reported that the ability of
bone marrow mononuclear cells to differentiate into endothelial
progenitor cells was strongly affected, resulting in reduced
proangiogenic potential.
20 In the same way, EPCs from type-1
or -2 diabetic patients evidenced a impaired proliferation and
adhesion and incorporation into vascular structures, supporting
the hypothesis of altered EPCs in diabetes
21,22
Tanii et al23 in this issue of Circulation Research used a model of severe hind limb ischemia to further investigate the mechanisms of microangiopathy in streptozotocin-induced diabetic mice (STZ-DM). Diabetic mice frequently lost their hind limbs at various levels after ischemia, whereas the nondiabetic mice did not. The authors showed a disturbance of the PDGF-BB/PKC axis, but not of impaired expression or efficiency of angiogenic factors. Hence, VEGF-A, VEGF-C, HGF, FGF-1, PDGF-A, and their receptors flk-1, flt-1, PDGFR
, and -ß gene expression were unaffected in STZ-DM. In addition, FGF-2 gene transfer resulted in the upregulation of endogenous VEGF and HGF, prevented limb amputation, and restored limb blood flow, suggesting that angiogenic responses were minimally impaired in the STZ-DM model. In contrast, the PDGF-B expression was reduced in the STZ-DM in correlation with AGEs accumulation and morphological abnormalities of newly formed capillaries (dissociation of pericytes from the capillaries in ischemic muscles). Supplementation of the PDGF-B gene expression and PKC inhibitors restored the tissue levels of PDGF-B and were effective in preventing auto-amputation (Figure).

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Graphical representation of the proposed mechanisms leading to neovascularization abnormalities in diabetes mellitus. Diabetes-induced AGE accumulation promotes PKC activation and subsequent reduction in PDGF-BB gene expression. At the same time, AGEs hamper extracellular matrix degradation. Supplementation of the PDGF-B gene expression and PKC inhibitors restored the tissue levels of PDGF-B and are effective in increasing neovascularization and preventing auto-amputation in diabetic mice.
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Many questions remain unanswered. Is PKC/PDGF-BB axis affected in other models of diabetes; how does a 50% reduction in PDGF-BB expression lead to pericytes dissociation; and what is the nature of the intracellular signaling involved in PKC-induced downregulation of PDGF-BB gene expression? How does an alteration in the expression of a single growth factor can induced abnormalities in neovascularization? With a disease as complex as diabetes, other factors are likely to be involved as well. However, these results strongly suggest that defects and impairments in the main proangiogenic factors are not obligatorily involved in the complication of severe ischemia occurring in this model of STZ-induced diabetes. In addition, the PKC/PDGF-BB axis could be a new molecular target for treating severe ischemic peripheral lesions in patients with diabetic complications.
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Acknowledgments
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B.L. and J.S.S. are supported by grants from INSERM and University
Paris 7.
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Footnotes
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The opinions expressed in this editorial are not necessarily
those of the editors or of the American Heart Association.
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