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Regular Articles |
From the Departments of Medicine (Cardiology) and Biomedical
Research,*
St. Elizabeth's Medical Center, Tufts University
School of Medicine, Boston, Massachusetts, and Department of Medicine
(Cardiology),
Duke University, Durham,
North Carolina
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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0.005). This impairment in blood flow
recovery persisted throughout the duration of the study with Doppler
flow ratio values at day 35 of 0.50 ± 0.05 versus
0.90 ± 0.07 in the NOD and C57 mice, respectively
(P 0.001). CD31 immunostaining confirmed the
laser Doppler data by showing a significant reduction in capillary
density in the NOD mice at 35 days after surgery (302 ± 4
capillaries/mm2 versus 782 ± 78 in C57
mice (P 0.005). The reduction in
neovascularization in the NOD mice was the result of a lower level of
vascular endothelial growth factor (VEGF) in the ischemic
tissues, as assessed by Northern blot, Western blot and
immunohistochemistry. The central role of VEGF was confirmed by showing
that normal levels of neovascularization (compared with C57) could be
achieved in NOD mice that had been supplemented for this growth factor
via intramuscular injection of an adenoviral vector encoding for VEGF.
We conclude that 1) diabetes impairs endogenous neovascularization of
ischemic tissues; 2) the impairment in new blood vessel formation
results from reduced expression of VEGF; and 3) cytokine
supplementation achieved by intramuscular adeno-VEGF gene transfer
restores neovascularization in a mouse model of diabetes.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The ability of the organism to spontaneously develop new collateral blood vessels constitutes an important response to vascular occlusive disease that determines in large part the severity of residual tissue ischemia, particularly when vascular obstructions are so extensive that direct revascularization techniques cannot be undertaken successfully. Although it is a common clinical observation that collateral vessel development is impaired in diabetic patients, including those with myocardial5 as well as lower extremity6 ischemia, no previous experimental study has specifically evaluated the effect of diabetes on angiogenesis in ischemic vascular diseases. Moreover, the mechanisms by which diabetes could limit the formation of new blood vessels remain largely undefined.
Recent studies have demonstrated that angiogenesis, facilitated via administration of angiogenic growth factors as recombinant protein therapy7-13 or gene transfer14-17 may be augmented in animal models of myocardial and limb ischemia. The impact of diabetes in these experimental models, however, was not tested. In the present study, we show that diabetes impairs angiogenesis in a murine model of unilateral limb ischemia. We also demonstrate that this impairment of neovascularization is caused by reduced expression of vascular endothelial growth factor (VEGF) that can be successfully addressed by intramuscular gene transfer.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All protocols were approved by St. Elizabeth's Institutional Animal Care and Use Committee. The development of angiogenesis in response to regional ischemia was investigated in nonobese diabetic (NOD) mice. These mice have previously been shown to develop a form of diabetes with clinical features similar to those of the human type-I, insulin-dependent diabetes mellitus.18,19 The NOD mice were treated with bovine insulin (2 units subcutanously three times a week) for the duration of the study. Despite insulin replacement, the mice remained hyperglycemic with urine glucose values >2000 mg/dl. The outcomes observed in the NOD mice were compared with C57BL/6 mice used previously as controls for NOD mice.18,19
Surgery
Unilateral hindlimb ischemia was created in NOD or C57BL/6 mice as previously described.20,21 The animals were anesthetized with pentobarbital (160 mg/kg intraperitoneally) following which an incision was performed in the skin overlying the middle portion of the left hindlimb. After ligation of the proximal end of the femoral artery, the distal portion of the saphenous artery was ligated and the artery, as well as all side-branches, were dissected free and excised. The skin was closed using a surgical stapler.
Monitoring of Hindlimb Blood Flow
After anesthesia, hair was removed from both legs using a depilatory cream, following which the mice were placed on a heating plate at 37°C for 10 minutes to minimize temperature variations.
Hindlimb perfusion was measured using a laser Doppler perfusion imager (LDPI) system (Lisca Inc., North Brunswick, NJ). The LDPI uses a beam from a 2-mW helium-neon laser that sequentially scans a 12 x 12 cm tissue surface to a depth of a few hundred microns. During the scanning procedure, the moving blood cells shift the frequency of incident light according to the Doppler principle. A photodiode collects the back-scattered light, and the original light intensity variations are transformed into voltage variations in the range of 0 to 10 V. A perfusion output value of 0 V was set to 0% perfusion, whereas 10 V was set to 100%. When the scanning procedure is terminated and the back-scattered light collected from all of the measured sites, a color-coded image representing the microvascular blood flow distribution appears on a monitor. The perfusion signal is split into six different intervals, each displayed in a separate color. Low or no perfusion is displayed in dark blue, whereas the highest perfusion interval is displayed in red. The stored perfusion values behind the color-coded pixels are then available for analysis.
Consecutive measurements were obtained after scanning the same region of interest (leg and foot) with LDPI. Color photographs were recorded and analysis performed by calculating the average perfusion of the ischemic and nonischemic foot. To account for variables such as ambient light and temperature, the results are expressed as the ratio of perfusion in the left (ischemic) versus right (normal) limb. Serial changes in perfusion have been previously shown to correlate with changes in capillary density and endothelial incorporation of bromodeoxyuridine (BrDU).20
Tissue Preparation
The mice were sacrificed at predetermined arbitrary time points after surgery with an overdose of sodium pentobarbital. For immunohistochemistry, whole ischemic and nonischemic limbs were immediately fixed in methanol overnight. After bones had been carefully removed, 3-µm thick tissue sections were cut and paraffin embedded. For total protein extraction, isolated tissue samples were rinsed in phosphate-buffered saline (PBS) to remove excess blood, snap-frozen in liquid nitrogen, and stored at -80°C until use.
Immunohistochemistry
Histological sections, 5 µm thick, prepared from paraffin-embedded tissue samples of the lower limbs were used for immunohistochemical analysis. Identification of endothelial cells was performed by immunohistochemical staining for platelet endothelial cell adhesion molecule-1 (PECAM-1 or CD31) using a rat monoclonal antibody (MAb) directed against mouse CD31 (Pharmingen, San Diego, CA). Immunohistochemical localization of VEGF was performed using a rabbit polyclonal antibody directed against human VEGF amino terminal peptides 1–20 (Santa Cruz Biotechnology, Santa Cruz, CA) that cross-reacts with murine VEGF.
Immunoperoxidase staining was performed as previously described.20,22 In brief, sections were incubated in 3% hydrogen peroxide to block endogenous peroxide activity. To prevent nonspecific antibody binding, sections were preincubated for 20 minutes in PBS containing 10% horse serum. Next, sections were incubated with the primary antibodies directed against either CD31 or VEGF at appropriate dilutions overnight at 4°C. Sections were then rinsed for 15 minutes with PBS, followed by incubation with biotinylated secondary antibody for 30 minutes at room temperature. After a 15-minute wash, sections were treated with streptavidin-horseradish peroxidase (HRP) complex (Biogenex, San Ramon, CA) at room temperature for 30 minutes. Sections were rinsed with PBS and incubated with 0.05% 3,3'-diaminobenzidine tetrahydrochloride dihydrate (for VEGF staining) or 3-amino-9-ethylcarbazole (for CD31 staining). Sections were finally counterstained with 20% Gill's hematoxylin and subsequently covered. Negative control slides were prepared by substituting preimmune rat serum for CD31 and preimmune rabbit serum for VEGF antibody staining.
Analysis of Capillary Density
Capillaries, identified by positive staining for CD31 and appropriate morphology, were counted by a single observer blinded to the treatment regimen under a 20x objective and a 5x lens to determine the capillary density (mean number of capillaries per square millimeter).20 A total of 20 different fields from the two muscles were randomly selected, and the number of capillaries were counted for each field.
Northern Blot Analysis of VEGF mRNA Expression
Total tissue RNA was isolated from ischemic hindlimb muscles of mice by phenol/chloroform extraction.23 Twenty µg of RNA/lane were separated by electrophoresis on 1% agarose gel containing formaldehyde and transferred to a nylon membrane (Hybond-N, Amersham) by blotting. The membrane was hybridized with 32P-labeled probe specific for VEGF, a 675-bp EcoRI/BglII fragment of plasmid pSVI.VEGF.21.24 Hybridization was carried out as previously described.23
Western Blot Analysis of VEGF Protein Expression
Whole-cell protein extracts were obtained after homogenization of ischemic and control muscles of both young and old animals. A total of 200 µg of protein per sample was separated on a 12% polyacrylamide gel and electroblotted on nitrocellulose membranes.25 The membrane was blocked with 10% nonfat dry milk in 0.2% Tween phosphate buffered saline (T-PBS) and then probed with 1:250 of rabbit polyclonal anti-human VEGF antibody (Sigma) for 3 hours at room temperature. After incubation with primary antibody, the blot was washed three times in T-PBS, followed by incubation for 1 hour with 1:4000 of anti-rabbit horseradish peroxidase IgG (Santa Cruz Biotechnology). The blot was then washed in T-PBS, and antigen-antibody complexes were visualized after incubation for 1 minute with enhanced luminescence reagent (Amersham) at room temperature, followed by exposure to Kodak XAR-5 film.
Intramuscular Adenoviral Transfection
Mice were transfected with E1-deleted recombinant adenovirus (1 x 109 pfu) expressing either LacZ containing a nuclear localization sequence (nls-LacZ) or murine VEGF cDNA. Transfection was performed by four direct intramuscular injections into the thigh muscles of the ischemic hindlimb using a 27-gauge needle at the time of surgery.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Hindlimb perfusion was evaluated postoperatively by serial LDPI
studies (Figure 1
).
Restoration of perfusion was significantly slower in NOD mice
versus controls. At day 14 after surgery, the ratio of blood
flow between the ischemic and the normal limb was 0.49 ± 0.04
compared with 0.73 ± 0.06 for the C57 mice
(P 0.005). This impairment in blood flow
recovery was consistent throughout the duration of the study, so that
perfusion remained impaired up to the time of sacrifice (day 35) with
values of 0.50 ± 0.05 versus 0.90 ± 0.07 in the
NOD and C57 mice, respectively (P 0.001).
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, there was a significant reduction in
capillary density in the NOD mice at 35 days postoperatively with
values of 302 ± 4 capillaries/mm2
versus 782 ± 78 for NOD mice versus C57
controls (P 0.005).
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At baseline (nonischemic hindlimbs, day 0), the level of VEGF mRNA
expression was almost undetectable both in C57 and NOD mice. However,
in ischemic hindlimbs, VEGF mRNA expression was significantly reduced
in NOD versus C57 mice, especially at day 7 and 14 after
surgery (Figure 3)
.
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Endogenous expression of VEGF protein was determined for NOD and
C57 mice by Western blot analysis of protein extracts obtained from
hindlimb muscles harvested at different time points postoperatively.
Figure 4A
shows the time course of VEGF
expression in NOD and C57 mice after operative induction of hindlimb
ischemia. In both C57 and NOD mice, VEGF levels were undetectable at
baseline (nonischemic hindlimbs, day 0). However, in ischemic
hindlimbs, the level of VEGF protein expression was significantly
reduced in NOD versus C57 mice from day 3 to day 14 after
surgery. Immunostaining confirmed the results of the Western blots by
showing a lower level of VEGF expression in the tissues retrieved from
NOD versus C57 mice at day 7 after surgery (Figure 4, B and C)
and identifying the skeletal myocytes as the cell source of VEGF
expression. The specificity of the immunostaining was confirmed using
negative controls (Figure 4C
, control) prepared in C57 and NOD mice by
substituting preimmune rabbit serum for VEGF antibody staining.
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We used an adenoviral vector encoding for the murine VEGF sequence
to provide replacement therapy for deficient VEGF expression in the NOD
mice. Adeno-VEGF was injected intramuscularly at a dose of 1 x
109
pfu immediately after the surgery
(n = 7). NOD mice injected with the same dose of an
adenoviral construct coding for nuclear-specific ß-galactosidase
(adeno-nls-LacZ) (n = 5) were
used as controls. Figure 5, A and B
illustrates the macroscopic and histological sections of ischemic
muscles stained with X-Gal solution 3 days after intramuscular
injection of the adeno-nls-LacZ construct. The
efficiency of the transfection was confirmed by the positive blue
staining of the myocyte nuclei. As shown on Figure 5C
, NOD mice
receiving VEGF replacement therapy showed significant improvement in
hindlimb perfusion as assessed by LDPI. At day 21 after surgery, the
ratio of ischemic to normal hindlimb blood flow was 0.9 ± 0.2 for
NOD mice transduced with adeno-VEGF versus 0.5 ± 0.1
for NOD mice receiving adeno-nls-LacZ
(P 0.05). This improvement in hindlimb
perfusion was consistent for the duration of the study with final
values of 1.0 ± 0.2 versus 0.5 ± 0.2 in the VEGF
and adeno-nls-LacZ mice, respectively
(P 0.05). These results were confirmed at the
microvascular level. As seen on Figure 6
,
there was a significant increase in capillary density in NOD mice
injected with adeno-VEGF (Figure 6A)
compared with mice receiving
adeno-nls-LacZ (Figure 6B
). Necropsy
examination disclosed the capillary density in adeno-VEGF-treated mice
to be 903 ± 224 capillaries/mm2
versus 326 ± 57 for
adeno-nls-LacZ-transduced mice (Figure 6C
, P 0.05).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mechanisms by which diabetes may affect angiogenesis are potentially diverse. Angiogenesis is a complex process that involves activation, migration, and proliferation of endothelial cells.30 Recent studies have documented that endothelium-dependent relaxation is impaired in both the peripheral and coronary arteries of insulin-dependent diabetic patients.31,32 In vitro studies of endothelial cells have also shown that a high glucose concentration is associated with decreased endothelial cell proliferation, cell cycle prologation, and alterations in endothelial cell cytoarchitecture.33-35 Taken together, these observations support the notion that endothelial dysfunction associated with diabetes could contribute to the impaired angiogenesis in the setting of tissue ischemia.
Growth factors, particularly endothelial cell mitogens, represent a second essential element in the promotion and regulation of angiogenensis. VEGF, an endothelial cell-specific mitogen has been shown to be a critical growth factor in therapeutic 7,8,11,12,16,17 and pathological26,36,37 angiogenesis. The absence of a single VEGF allele in the developing embryo is sufficient to prohibit vascular development, and VEGF appears to lie downstream of several, if not all, other angiogenic cytokines.24,38-40 In the present study, we showed that the magnitude of VEGF expression in ischemic hindlimbs of diabetic mice was significantly reduced in comparison with that observed in normal C57 mice. The lower levels of VEGF expression in NOD mice was documented by Northern blot, Western blot, and immunohistochemical studies of tissues isolated from the ischemic hindlimbs. Interestingly, a similar defect in VEGF regulation has also been reported in diabetic mice in the context of wound healing.41 These observations contrast with studies on angiogenesis in the context of diabetic retinopathy. In this situation, high levels of VEGF have been identified in ocular fluids of diabetic patients.26 The mechanisms by which VEGF expression could be different from one tissue to the other are not known. It is possible that the transcriptional or posttranscriptional regulation of VEGF could vary depending on the cell type (skeletal myocytes versus retinal cells). Alternatively, differences in the degree and type of ischemia (chronic versus acute) could account for the differences in VEGF expression in different tissues.
The pivotal role of VEGF in diabetes-related impairment of angiogenesis was confirmed by replacement of this growth factor in the NOD mice. Using direct intramuscular injection of a replication-deficient adenovirus coding for murine VEGF, we demonstrated a statistically significant improvement in both hindlimb blood flow and capillary density in diabetic mice, achieving values similar to those of normal C57 mice. Supplementation of angiogenic growth factors as recombinant protein therapy7-13 or gene transfer14-17 has been used in animal models of myocardial and limb ischemia to augment the development of new vessels. More recently, this strategy has been used to amplify neovascularization in selected patients with peripheral17,42 and coronary artery disease.43 The extent to which the use of such therapy may be affected by specific risk factors in patients with vascular diseases is not known. We have recently shown that endogenous hypercholesterolemia impairs angiogenesis, but does not preclude a favorable response to therapeutic angiogenesis.44,45 Similarly, whereas aging is associated with impaired angiogenesis, it does not preclude augmented neovascularization in response to exogenous VEGF administration.46 Diabetics represent an additional large subgroup of patients with a high incidence of cardiovascular diseases. The present series of experiments suggests that such patients, in whom the development of collateral blood vessels in response to tissue ischemia may be impaired because of insufficient VEGF expression, may benefit from a strategy of VEGF replacement. It is appropriate, however, to underscore the fact that the present study involves a total time frame of 35 days; whether such success can be duplicated indefinitely in humans with a multiyear history of insulin-requiring diabetes remains to be determined.
Finally, the results of these experiments may have implications for the high incidence of restenosis47 and poor long-term outcomes,48 which have been reported for diabetics treated by percutaneous revascularization. Experimental work from our laboratory25 and others49,50 has suggested a role for VEGF in the maintenance of endothelial integrity and consequently primary or secondary neointimal thickening. If VEGF expression by the arterial smooth muscle cells of diabetic patients is compromised to the extent observed in the skeletal myocytes of the diabetic mouse hindlimb, the consequent disruption of endothelial integrity may promote recurrent luminal narrowing.
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Footnotes |
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Supported in part by grants HL53354 and HL57516 (J. M. Isner) from the National Heart, Lung, and Blood Institute, the National Institutes of Health, Bethesda, MD and the E. L. Weigand Foundation, Reno, NV. A. Rivard is supported by a grant from the Heart and Stroke Foundation of Canada.
Accepted for publication October 26, 1998.
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65 years (Report from Coronary Artery Surgery Study (CASS) Registry). Am J Cardiol 1994, 74:334[Medline]
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N. Ouchi, R. Shibata, and K. Walsh AMP-Activated Protein Kinase Signaling Stimulates VEGF Expression and Angiogenesis in Skeletal Muscle Circ. Res., April 29, 2005; 96(8): 838 - 846. [Abstract] [Full Text] [PDF]
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 Y.-s. Yoon, S. Uchida, O. Masuo, M. Cejna, J.-S. Park, H.-c. Gwon, R. Kirchmair, F. Bahlman, D. Walter, C. Curry, et al. Progressive Attenuation of Myocardial Vascular Endothelial Growth Factor Expression Is a Seminal Event in Diabetic Cardiomyopathy: Restoration of Microvascular Homeostasis and Recovery of Cardiac Function in Diabetic Cardiomyopathy After Replenishment of Local Vascular Endothelial Growth Factor Circulation, April 26, 2005; 111(16): 2073 - 2085. [Abstract] [Full Text] [PDF]
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 N. P. Kadoglou, S. S. Daskalopoulou, D. Perrea, and C. D. Liapis Matrix Metalloproteinases and Diabetic Vascular Complications Angiology, March 1, 2005; 56(2): 173 - 189. [Abstract] [PDF]
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J. Waltenberger Growth factor signal transduction defects in the cardiovascular system Cardiovasc Res, February 15, 2005; 65(3): 574 - 580. [Abstract] [Full Text] [PDF]
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 M. Bosch-Marce, R. Pola, A. B Wecker, M. Silver, A. Weber, C. Luedemann, C. Curry, T. Murayama, M. Kearney, Y.-s. Yoon, et al. Hyperhomocyst(e)inemia impairs angiogenesis in a murine model of limb ischemia Vascular Medicine, February 1, 2005; 10(1): 15 - 22. [Abstract] [PDF]
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T. G. Ebrahimian, R. Tamarat, M. Clergue, M. Duriez, B. I. Levy, and J.-S. Silvestre Dual Effect of Angiotensin-Converting Enzyme Inhibition on Angiogenesis in Type 1 Diabetic Mice Arterioscler. Thromb. Vasc. Biol., January 1, 2005; 25(1): 65 - 70. [Abstract] [Full Text] [PDF]
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D. J Collinson, R. Rea, and R. Donnelly Masterclass series in peripheral arterial disease: Vascular risk: diabetes Vascular Medicine, November 1, 2004; 9(4): 307 - 310. [PDF]
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K. F. Kusano, K. L. Allendoerfer, W. Munger, R. Pola, M. Bosch-Marce, R. Kirchmair, Y.-s. Yoon, C. Curry, M. Silver, M. Kearney, et al. Sonic Hedgehog Induces Arteriogenesis in Diabetic Vasa Nervorum and Restores Function in Diabetic Neuropathy Arterioscler. Thromb. Vasc. Biol., November 1, 2004; 24(11): 2102 - 2107. [Abstract] [Full Text] [PDF]
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 T. Asahara and A. Kawamoto Endothelial progenitor cells for postnatal vasculogenesis Am J Physiol Cell Physiol, September 1, 2004; 287(3): C572 - C579. [Abstract] [Full Text] [PDF]
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 R. E. Waters, R. L. Terjung, K. G. Peters, and B. H. Annex Preclinical models of human peripheral arterial occlusive disease: implications for investigation of therapeutic agents J Appl Physiol, August 1, 2004; 97(2): 773 - 780. [Abstract] [Full Text] [PDF]
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N. Takeda, K. Maemura, Y. Imai, T. Harada, D. Kawanami, T. Nojiri, I. Manabe, and R. Nagai Endothelial PAS Domain Protein 1 Gene Promotes Angiogenesis Through the Transactivation of Both Vascular Endothelial Growth Factor and Its Receptor, Flt-1 Circ. Res., July 23, 2004; 95(2): 146 - 153. [Abstract] [Full Text] [PDF]
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D. W. Losordo and S. Dimmeler Therapeutic Angiogenesis and Vasculogenesis for Ischemic Disease: Part II: Cell-Based Therapies Circulation, June 8, 2004; 109(22): 2692 - 2697. [Full Text] [PDF]
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 C. Theopold, F. Yao, and E. Eriksson Gene Therapy in the Treatment of Lower Extremity Wounds International Journal of Lower Extremity Wounds, June 1, 2004; 3(2): 69 - 79. [Abstract] [PDF]
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R. D. Galiano, O. M. Tepper, C. R. Pelo, K. A. Bhatt, M. Callaghan, N. Bastidas, S. Bunting, H. G. Steinmetz, and G. C. Gurtner Topical Vascular Endothelial Growth Factor Accelerates Diabetic Wound Healing through Increased Angiogenesis and by Mobilizing and Recruiting Bone Marrow-Derived Cells Am. J. Pathol., June 1, 2004; 164(6): 1935 - 1947. [Abstract] [Full Text] [PDF]
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C. Emanueli, G. Graiani, M. B. Salis, S. Gadau, E. Desortes, and P. Madeddu Prophylactic Gene Therapy With Human Tissue Kallikrein Ameliorates Limb Ischemia Recovery in Type 1 Diabetic Mice Diabetes, April 1, 2004; 53(4): 1096 - 1103. [Abstract] [Full Text] [PDF]
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E. Larger, M. Marre, P. Corvol, and J.-M. Gasc Hyperglycemia-Induced Defects in Angiogenesis in the Chicken Chorioallantoic Membrane Model Diabetes, March 1, 2004; 53(3): 752 - 761. [Abstract] [Full Text] [PDF]
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R. Tamarat, J.-S. Silvestre, S. Le Ricousse-Roussanne, V. Barateau, L. Lecomte-Raclet, M. Clergue, M. Duriez, G. Tobelem, and B. I. Levy Impairment in Ischemia-Induced Neovascularization in Diabetes: Bone Marrow Mononuclear Cell Dysfunction and Therapeutic Potential of Placenta Growth Factor Treatment Am. J. Pathol., February 1, 2004; 164(2): 457 - 466. [Abstract] [Full Text] [PDF]
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N. Ouchi, H. Kobayashi, S. Kihara, M. Kumada, K. Sato, T. Inoue, T. Funahashi, and K. Walsh Adiponectin Stimulates Angiogenesis by Promoting Cross-talk between AMP-activated Protein Kinase and Akt Signaling in Endothelial Cells J. Biol. Chem., January 9, 2004; 279(2): 1304 - 1309. [Abstract] [Full Text] [PDF]
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S. L. Hansen, C. A. Myers, A. Charboneau, D. M. Young, and N. Boudreau HoxD3 Accelerates Wound Healing in Diabetic Mice Am. J. Pathol., December 1, 2003; 163(6): 2421 - 2431. [Abstract] [Full Text]
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Z. Y. Jiang, Z. He, B. L. King, T. Kuroki, D. M. Opland, K. Suzuma, I. Suzuma, K. Ueki, R. N. Kulkarni, C. R. Kahn, et al. Characterization of Multiple Signaling Pathways of Insulin in the Regulation of Vascular Endothelial Growth Factor Expression in Vascular Cells and Angiogenesis J. Biol. Chem., August 22, 2003; 278(34): 31964 - 31971. [Abstract] [Full Text] [PDF]
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 R. Tamarat, J.-S. Silvestre, M. Huijberts, J. Benessiano, T. G. Ebrahimian, M. Duriez, M.-P. Wautier, J. L. Wautier, and B. I. Levy Blockade of advanced glycation end-product formation restores ischemia-induced angiogenesis in diabetic mice PNAS, July 8, 2003; 100(14): 8555 - 8560. [Abstract] [Full Text] [PDF]
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H. Masuda and T. Asahara Post-natal endothelial progenitor cells for neovascularization in tissue regeneration Cardiovasc Res, May 1, 2003; 58(2): 390 - 398. [Abstract] [Full Text] [PDF]
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A. Roguin, A. Avivi, S. Nitecki, I. Rubinstein, N. S. Levy, Z. A. Abassi, M. B. Resnick, O. Lache, M. Melamed-Frank, A. Joel, et al. Restoration of blood flow by using continuous perimuscular infiltration of plasmid DNA encoding subterranean mole rat Spalax ehrenbergi VEGF PNAS, April 15, 2003; 100(8): 4644 - 4648. [Abstract] [Full Text] [PDF]
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O. Z. Lerman, R. D. Galiano, M. Armour, J. P. Levine, and G. C. Gurtner Cellular Dysfunction in the Diabetic Fibroblast: Impairment in Migration, Vascular Endothelial Growth Factor Production, and Response to Hypoxia Am. J. Pathol., January 1, 2003; 162(1): 303 - 312. [Abstract] [Full Text] [PDF]
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K. Hirata, T.-S. Li, M. Nishida, H. Ito, M. Matsuzaki, S. Kasaoka, and K. Hamano Autologous bone marrow cell implantation as therapeutic angiogenesis for ischemic hindlimb in diabetic rat model Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H66 - H70. [Abstract] [Full Text] [PDF]
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O. M. Tepper, R. D. Galiano, J. M. Capla, C. Kalka, P. J. Gagne, G. R. Jacobowitz, J. P. Levine, and G. C. Gurtner Human Endothelial Progenitor Cells From Type II Diabetics Exhibit Impaired Proliferation, Adhesion, and Incorporation Into Vascular Structures Circulation, November 26, 2002; 106(22): 2781 - 2786. [Abstract] [Full Text] [PDF]
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P. Janiak, P. Lainee, Y. Grataloup, C.-E. Luyt, J.-P. Bidouard, J.-B. Michel, S. E O'Connor, and J.-M. Herbert Serotonin receptor blockade improves distal perfusion after lower limb ischemia in the fatty Zucker rat Cardiovasc Res, November 1, 2002; 56(2): 293 - 302. [Abstract] [Full Text] [PDF]
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S. Murasawa, J. Llevadot, M. Silver, J. M. Isner, D. W. Losordo, and T. Asahara Constitutive Human Telomerase Reverse Transcriptase Expression Enhances Regenerative Properties of Endothelial Progenitor Cells Circulation, August 27, 2002; 106(9): 1133 - 1139. [Abstract] [Full Text] [PDF]
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C. Emanueli, M. B. Salis, A. Pinna, T. Stacca, A. F. Milia, A. Spano, J. Chao, L. Chao, L. Sciola, and P. Madeddu Prevention of Diabetes-Induced Microangiopathy by Human Tissue Kallikrein Gene Transfer Circulation, August 20, 2002; 106(8): 993 - 999. [Abstract] [Full Text] [PDF]
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F. Facchiano, A. Lentini, V. Fogliano, S. Mancarella, C. Rossi, A. Facchiano, and M. C. Capogrossi Sugar-Induced Modification of Fibroblast Growth Factor 2 Reduces Its Angiogenic Activity in Vivo Am. J. Pathol., August 1, 2002; 161(2): 531 - 541. [Abstract] [Full Text] [PDF]
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R. S. Smith Jr, K.-F. Lin, J. Agata, L. Chao, and J. Chao Human Endothelial Nitric Oxide Synthase Gene Delivery Promotes Angiogenesis in a Rat Model of Hindlimb Ischemia Arterioscler. Thromb. Vasc. Biol., August 1, 2002; 22(8): 1279 - 1285. [Abstract] [Full Text] [PDF]
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 S. Marchetti, C. Gimond, K. Iljin, C. Bourcier, K. Alitalo, J. Pouyssegur, and G. Pages Endothelial cells genetically selected from differentiating mouse embryonic stem cells incorporate at sites of neovascularization in vivo J. Cell Sci., May 15, 2002; 115(10): 2075 - 2085. [Abstract] [Full Text] [PDF]
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Q. Dai, M. A Thompson, A. M Pippen, H. Cherwek, D. A Taylor, and B. H Annex Alterations in endothelial cell proliferation and apoptosis contribute to vascular remodeling following hind-limb ischemia in rabbits Vascular Medicine, May 1, 2002; 7(2): 87 - 91. [Abstract] [PDF]
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C. Emanueli, M. Bonaria Salis, T. Stacca, G. Pintus, R. Kirchmair, J. M. Isner, A. Pinna, L. Gaspa, D. Regoli, C. Cayla, et al. Targeting Kinin B1 Receptor for Therapeutic Neovascularization Circulation, January 22, 2002; 105(3): 360 - 366. [Abstract] [Full Text] [PDF]
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E. Chou, I. Suzuma, K. J. Way, D. Opland, A. C. Clermont, K. Naruse, K. Suzuma, N. L. Bowling, C. J. Vlahos, L. P. Aiello, et al. Decreased Cardiac Expression of Vascular Endothelial Growth Factor and Its Receptors in Insulin-Resistant and Diabetic States: A Possible Explanation for Impaired Collateral Formation in Cardiac Tissue Circulation, January 22, 2002; 105(3): 373 - 379. [Abstract] [Full Text] [PDF]
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 K.S. MOULTON Plaque Angiogenesis: Its Functions and Regulation Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 471 - 482. [Abstract] [PDF]
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 Z S Kyriakides, S Psychari, N Chrysomallis, M Georgiadis, E Sbarouni, and D T Kremastinos Type II diabetes does not prevent the recruitment of collateral vessels and the normal reduction of myocardial ischaemia on repeated balloon inflations during angioplasty Heart, January 1, 2002; 87(1): 61 - 66. [Abstract] [Full Text] [PDF]
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 S. B. Freedman and J. M. Isner Therapeutic Angiogenesis for Coronary Artery Disease Ann Intern Med, January 1, 2002; 136(1): 54 - 71. [Abstract] [Full Text] [PDF]
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P. Porcu, C. Emanueli, M. Kapatsoris, J. Chao, L. Chao, and P. Madeddu Reversal of Angiogenic Growth Factor Upregulation by Revascularization of Lower Limb Ischemia Circulation, January 1, 2002; 105(1): 67 - 72. [Abstract] [Full Text] [PDF]
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Y. Taniyama, R. Morishita, K. Hiraoka, M. Aoki, H. Nakagami, K. Yamasaki, K. Matsumoto, T. Nakamura, Y. Kaneda, and T. Ogihara Therapeutic Angiogenesis Induced by Human Hepatocyte Growth Factor Gene in Rat Diabetic Hind Limb Ischemia Model: Molecular Mechanisms of Delayed Angiogenesis in Diabetes Circulation, November 6, 2001; 104(19): 2344 - 2350. [Abstract] [Full Text] [PDF]
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S. Takeshita, H. Tomiyama, N. Yokoyama, Y. Kawamura, T. Furukawa, Y. Ishigai, T. Shibano, T. Isshiki, and T. Sato Angiotensin-converting enzyme inhibition improves defective angiogenesis in the ischemic limb of spontaneously hypertensive rats Cardiovasc Res, November 1, 2001; 52(2): 314 - 320. [Abstract] [Full Text] [PDF]
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 D. A. Elson, G. Thurston, L. E. Huang, D. G. Ginzinger, D. M. McDonald, R. S. Johnson, and J. M. Arbeit Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1{alpha} Genes & Dev., October 1, 2001; 15(19): 2520 - 2532. [Abstract] [Full Text] [PDF]
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R Tabibiazar and S.G Rockson Angiogenesis and the ischaemic heart Eur. Heart J., June 1, 2001; 22(11): 903 - 918. [PDF]
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 Z. T. Bloomgarden European Association for the Study of Diabetes Annual Meeting, 2000: Pathogenesis of type 2 diabetes, vascular disease, and neuropathy Diabetes Care, June 1, 2001; 24(6): 1115 - 1119. [Full Text]
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 D. Simovic, J. M. Isner, A. H. Ropper, A. Pieczek, and D. H. Weinberg Improvement in Chronic Ischemic Neuropathy After Intramuscular phVEGF165 Gene Transfer in Patients With Critical Limb Ischemia Arch Neurol, May 1, 2001; 58(5): 761 - 768. [Abstract] [Full Text] [PDF]
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L. E. Benjamin Glucose, VEGF-A, and Diabetic Complications Am. J. Pathol., April 1, 2001; 158(4): 1181 - 1184. [Full Text] [PDF]
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J. Waltenberger Impaired collateral vessel development in diabetes: potential cellular mechanisms and therapeutic implications Cardiovasc Res, February 16, 2001; 49(3): 554 - 560. [Abstract] [Full Text] [PDF]
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 C. Kalka, H. Tehrani, B. Laudenberg, P. R. Vale, J. M. Isner, T. Asahara, and J. F. Symes VEGF gene transfer mobilizes endothelial progenitor cells in patients with inoperable coronary disease Ann. Thorac. Surg., September 1, 2000; 70(3): 829 - 834. [Abstract] [Full Text] [PDF]
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 A. W. Griffioen and G. Molema Angiogenesis: Potentials for Pharmacologic Intervention in the Treatment of Cancer, Cardiovascular Diseases, and Chronic Inflammation Pharmacol. Rev., June 1, 2000; 52(2): 237 - 268. [Abstract] [Full Text] [PDF]
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G. Walter, E. R. Barton, and H. L. Sweeney Noninvasive measurement of gene expression in skeletal muscle PNAS, May 9, 2000; 97(10): 5151 - 5155. [Abstract] [Full Text] [PDF]
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P. Sinnaeve, O. Varenne, D. Collen, and S. Janssens Gene therapy in the cardiovascular system: an update Cardiovasc Res, December 1, 1999; 44(3): 498 - 506. [Abstract] [Full Text] [PDF]
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C. Kalka, H. Masuda, T. Takahashi, W. M. Kalka-Moll, M. Silver, M. Kearney, T. Li, J. M. Isner, and T. Asahara Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization PNAS, March 28, 2000; 97(7): 3422 - 3427. [Abstract] [Full Text] [PDF]
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 S. C. FRANCIS, M. K. RAIZADA, A. A. MANGI, L. G. MELO, V. J. DZAU, P. R. VALE, J. M. ISNER, D. W. LOSORDO, J. CHAO, M. J. KATOVICH, et al. Genetic targeting for cardiovascular therapeutics: are we near the summit or just beginning the climb? Physiol Genomics, December 21, 2001; 7(2): 79 - 94. [Abstract] [Full Text] [PDF]
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