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Am J Physiol Heart Circ Physiol 290: H1387-H1392, 2006. First published December 9, 2005; doi:10.1152/ajpheart.00652.2005
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Regulation and Function of Stem Cells in the Cardiovascular System

Synergistic targeting with bone marrow-derived cells and PDGF improves diabetic vascular function

David A. Klibansky, Andrew Chin, Inga J. Duignan, and Jay M. Edelberg

Departments of Medicine and of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York

Submitted 17 June 2005 ; accepted in final form 21 November 2005


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Diabetes mellitus is associated with an increased risk of vascular disease, with significant alterations in systemic endothelial progenitor cells (EPCs) and peripheral vascular function. To identify the contribution of the different vascular compartments in the diabetic impairment of vascularization, we employed streptozotocin- and control-treated 3-mo-old C57Bl/6 mice in an isogeneic pinnal cardiac allograft model, revealing a significant delay in vascularization of wild-type cardiac tissue transplanted into diabetic mice. To investigate the basis of this impairment, the function of diabetic bone marrow cells was tested by transplantation of bone marrow cells isolated from diabetic and control mice into intact, unirradiated 18-mo-old C57Bl/6 mice, which have impaired function of both EPCs and peripheral endothelial cells. Importantly, cells derived from control, but not diabetic, bone marrow integrated into transplanted cardiac allografts. To assess the contribution of diabetic changes in the local vasculature, diabetic mice were treated with pinnal injections of platelet-derived growth factor (PDGF)-AB, which promotes cardiac angiogenesis in wild-type mice. However, whereas PDGF-AB enhanced allograft function in control mice, the activity of the cardiac transplants in the PDGF-AB-treated diabetic mice was significantly decreased. To decipher the potential interactions between systemic bone marrow-derived cells and local vascular pathways, diabetic mice were transplanted with wild-type bone marrow cells with or without PDGF-AB pinnal pretreatment, resulting in improved allograft function and donor cell recruitment only in the combination treatment arm. Overall, these studies show that the diabetic impairment in cardiac angiogenesis can be reversed by targeting the synergism between local trophic pathways and systemic cell function.

diabetes mellitus; endothelial progenitor cells; platelet-derived growth factor; aging; heart

DIABETES MELLITUS IS ASSOCIATED with micro- and macrovascular dysfunction and disease (20), including impaired cardiac vascular angiogenesis that may contribute to severe clinical cardiovascular disease (1, 9, 30). Mechanistically, diabetes has been linked to altered nitric oxide signaling (5, 27), oxidative stress (17, 31), and the formation of advanced glycation end products (3, 4, 18), as well as dyslipidemia (2, 13). However, despite the identification of such disease-related mechanisms, the specific cell targets mediating the impairment in vascular function remain to be defined.

Diabetes has been shown to impact the function of both endothelial cells as well as endothelial progenitor cells (EPCs). Clinical investigations have revealed that diabetes is associated with impaired endothelial cell migration in vitro (10) as well as impaired endothelium-dependent vasodilation in vivo (12). Diabetes has additionally been linked with decreased numbers of circulating EPCs as well as impaired angiogenic function of diabetic-derived EPCs (15). Moreover, compared with cells from healthy donors, EPCs isolated from diabetic patients exhibit impaired ability to bind to activated endothelial cells in culture and promote blood flow to vascular structures in ischemic limbs (22, 23). Such changes in endothelial-EPC interactions may be critical in the mechanisms underlying the impairment in cardiac vascular function and may contribute to the inverse correlation of EPC levels and cardiovascular disease risk (24). Indeed, the local administration of bone marrow-derived CD34-positive (CD34+) cells from control animals improves blood flow and wound healing in hindlimb ischemia and skin wound models in diabetic animals (16, 19), suggesting that a primary defect in EPCs may similarly contribute to impaired cardiac angiogenic function associated with diabetes.

The present investigations sought to define the vascular and endothelial compartment(s) underlying the diabetic dysregulation in vascular function, employing a cardiac allograft model which allows for the assessment of the specific contribution of local vascular and EPC-mediated cardiac angiogenic activity in the diabetic milieu while maintaining a wild-type myocardial environment. Previously, this research approach has been utilized to elucidate the role of impaired expression of platelet-derived growth factor (PDGF) by endothelial cells as well as EPCs in age-associated depression in cardiac angiogenic function (7, 8). Specifically, we hypothesized that studies in the pinnal allograft model would identify the vascular/endothelial compartment(s) that underlie the diabetic impairment in cardiac vascular function. Indeed, because this model has facilitated the advancement of novel cardioprotective approaches (7, 29), the results of pinnal allograft studies in diabetic mice could direct the development of molecular- and/or cellular-based approaches that may reduce diabetic-related cardiovascular diseases.


   MATERIALS AND METHODS
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 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals. All experiments involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Weill Medical College of Cornell University, which follows federal and state guidelines.

Diabetic induction. To generate diabetic mice, 3-mo-old male C57Bl/6 and B6.129Sv-Gtrosa26 (Rosa) mice were randomized to receive injections intraperitoneally with 40 mg/kg of streptozotocin (STZ) dissolved in 0.1 M sodium citrate buffer, pH 4.5, or vehicle only in the case of control animals, for 5 days as previously described (14). Three days after the final injection, the animal's blood glucose was measured by using an Accu-Chek II Advantage Glucometer (Roche Diagnostics). Diabetic animals with a serum level of glucose <225 mg/dl received an additional 2 days of STZ at the same dose. Testing was performed again at 4 and 8 wk, and animals with blood glucose levels <250 mg/dl were excluded from the study.

Cardiac allograft angiogenesis assay. To test the effects of diabetes on cardiac angiogenic function and its potential modulation of vascular function in different host mice, we employed a cardiac allograft model. This model allows for the assessment of disease-associated alterations in cardiac angiogenesis while controlling for the functional and structural integrity of the (wild-type neonatal) heart being vascularized (6–8). Briefly, 8 wk after STZ or control treatment, the mice were transplanted by a blinded investigator with cardiac allografts explanted from neonatal (1 day old) C57Bl/6 pups, which were inserted into a subcutaneous pocket that had been surgically created in the host pinnae as previously described (6–8). On posttransplant days 3 and 7, the allograft transplants were tested for viability and function as assessed by a blinded investigator scoring visual integrity and electrocardiographic (ECG) activity in the transplanted pinnae as previously described (6). A transplant was considered functional only if it was both visually intact and demonstrated sustained chronotropic activity of ≥1 Hz. Blood flow to the cardiac allografts in the control and diabetic hosts was also quantified on posttransplant days 3 and 7 by a blinded investigator employing laser-Doppler measurements with a single-channel Advance Laser Flowmeter ALF21/21D (Advance, Tokyo, Japan) equipped with a contact C-Probe (range: 0–100 ml·min–1·100 g tissue–1) as previously described (6). On the basis of the average mass of the neonatal cardiac tissue transplanted into the pinnae (2 mg), the flow into the allografts was calculated from the laser-Doppler measurements (in ml·min–1·100 g tissue–1). Additional sets of both diabetic and control animals received injections of 100 ng/10 µl of PDGF-AB into the pinnae 24 h before allograft transplantation to assess the potential reversibility of vascular defects in the diabetic animal. The sample size was n ≥ 10 per study condition.

Bone marrow-mediated cardiac angiogenic activity. To investigate diabetes-associated defects in the ability of bone marrow-derived cells to promote cardiac angiogenic activity, transplantation of bone marrow cells derived from young diabetic donor animals into angiogenically deficient senescent (18 mo old) hosts was performed. Briefly, bone marrow cells isolated from diabetic or control C57Bl/6 as well as diabetic or control Rosa mice were injected (1 x 106 cells/injection) into the tail veins of 18-mo-old intact, unirradiated, C57Bl/6 female host mice as previously described (8). Mice receiving PBS injections served as controls. Cardiac angiogenesis was tested 7 days after bone marrow transplantation by means of the cardiac allograft assay. The sample size was n ≥ 7 per study condition.

To further test the potential of bone marrow-derived cells to reverse diabetes-associated vascular dysfunction, sets of diabetic animals were injected with bone marrow cells isolated from young male control Rosa mice. Groups of control and diabetic mice pretreated with PDGF received bone marrow-derived cells (1 x 106 cells/injection) followed by cardiac allograft transplantation 7 days later as described above (sample size was n ≥ 10 per study condition).

Animals were then euthanized 7 days after cardiac allograft transplantation, and the animal's femurs and tibias as well as pinnae containing the allograft were extracted, fixed, and evaluated for beta-galactosidase activity by incubation with X-gal and/or von Willebrand factor (vWF) similar to as previously described (8). The relative density of transplanted beta-galactosidase + Rosa-derived cells present in host marrow and pinnal cardiac allografts was quantified by a blinded investigator calculating the number of positively staining cells per high power field (x40 magnification) in eight fields containing transplanted cells (≥3 tissue samples per condition).

Statistics. Data are presented as means ± SE. Analysis of average blood flow and Rosa cell quantification was performed by using ANOVA with post hoc analysis of group differences using a Bonferroni corrected t-test. Comparison of average transplant function was performed by using binomial distribution statistical methods. A value of P ≤ 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Impaired cardiac allograft function in diabetic hosts. To investigate the potential impact of diabetes on cardiac angiogenic function without affecting endogenous cardiac function and related physiology, our studies employed a cardiac allograft transplantation model. In this assay, syngeneic neonatal hearts are engrafted subcutanenously into the pinnae of host mice. Through host-dependent angiogenesis, the cardiac tissue is vascularized, demonstrating independent chronotropic activity as a physiological measure of allograft function and viability (Fig. 1A). When compared with transplants in control hosts, the induction of chronotropic activity in the diabetic engrafted hearts was significantly delayed (Fig. 1B), which correlated with significantly lower blood flow to the cardiac tissue 3 days after transplantation. Notably, by 7 days, the chronotropic activity and blood flow to the transplants in the diabetic hosts were similar to measurements in control mice. On the basis of the importance of tissue vascularization for electrical activity of the cardiac allografts (6–8), these findings suggested that diabetes may impair cardiac angiogenic function. Moreover, on the basis of the capacity of this model to allow for the isolation of specific components of angiogenesis, the cardiac allograft assay could facilitate the evaluation of the mechanisms and potential reversal of the functional alterations in the cardiac angiogenic function of the diabetic host.


Figure 1
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  		Fig. 1. Delayed cardiac allograft function in diabetic hosts. A: representative cardiac allograft (within dashed white circle) that was transplanted into subcutaneous tissue of a control 3-mo-old murine host with ECG evidence of allograft function. B: quantification of total percentage of functional allograft scored by evidence of independent ECG activity measured at 3 and 7 days after cardiac allograft transplantation into control and diabetic mice. C: quantification of average pinnal blood flow to cardiac allografts measured at 3 and 7 days after cardiac allograft transplantation into control and diabetic mice. *P < 0.05; n ≥ 10 mice per group.

 
Diabetic impairment in bone marrow-mediated cardiac angiogenesis. To identify the potential cellular basis of the impairment in cardiac angiogenic function in the diabetic mice, our studies attempted to isolate the impact of diabetes on bone marrow-derived, cell-mediated function in a senescent transplant model. To this end, we have previously demonstrated that EPCs derived from transplanted young control bone marrow cells home to the bone marrow of intact, unirradiated syngeneic 18-mo-old mice and give rise to EPCs that can restore senescent cardiac angiogenic function (8). In this model, cells from diabetic and control mice revealed a similar capacity to home to the bone marrow of the aging mice (Fig. 2). However, cells derived from the wild-type bone marrow demonstrated a significantly greater capacity to home to the pinnal cardiac allografts and promoted the chronotropic function of the transplanted cardiac tissue, suggesting that alterations in bone marrow-derived cells, including EPCs, may contribute to the diabetic impairment in cardiac angiogenic function.


Figure 2
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  		Fig. 2. Assessment of ability of diabetic-derived donor cells to promote cardiac angiogenesis. A: representative photographs of pinnae of 18-mo-old angiogenically deficient senescent mice administered no bone marrow (No BM) or bone marrow from control (CTL BM) or diabetic donors (DM BM) before cardiac allograft transplantation with representative ECGs below (5-s intervals shown). Of note, allografts without pretransplantation of young bone marrow cells resulted in loss of cardiac transplants and surrounding pinnal tissue. Transplants with young control bone marrow were intact with a high percentage of ECG (functional) activity. Transplants in mice receiving bone marrow from diabetic mice were intact but lacked robust ECG function. B: quantification of percentage of allograft function 7 days after allograft transplantation in animals receiving No BM, CTL BM, and DM BM. *P < 0.05 vs. No BM; n ≥ 7 mice per group. C: representative micrographs 7 days after cardiac allograft transplantation from 18-mo-old host mice administered Rosa control or diabetic bone marrow-derived cells. Eosin-stained slides demonstrate incorporation of transplanted cells into host femur and peripheral pinnae. D: quantification of density of beta-galactosidase (beta-Gal)-positive (+) donor cells present in host femur and pinnae scored per x40 high-power field (HPF). *P < 0.05 vs. CTL BM.

 
Diabetic alterations in peripheral vascular function. Our studies then focused on the changes in local vascular function that could contribute to the diabetic impairment in cardiac angiogenic function. On the basis of previous studies demonstrating the capacity of local pinnal treatment with PDGF-AB to improve both cardiac blood flow (6) and cardiac function (7), the diabetic mice were pretreated with PDGF-AB 1 day before cardiac transplantation. PDGF-AB enhanced the function of the cardiac transplants in the control mice, similar to as we previously reported (6, 7) (Fig. 3). Importantly, however, PDGF-AB not only did not improve the function of the cardiac allografts in the diabetic hosts but resulted in a significant decrease in the function of the transplants (Fig. 3).


Figure 3
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  		Fig. 3. Assessment of allograft ECG activity in control and diabetic mice treated by transplantation of control bone marrow (BMT) (without prior myeloablation) and/or pinnal injection of PDGF-AB before cardiac allograft transplantation. Total percentage of transplants with independent, normal ECG activity was scored at 3 (3d) and 7 (7d) days after cardiac allograft transplantation. *P < 0.05 vs. diabetic and control alone (7d); **P < 0.05 vs. control alone (3d); n ≥ 10 mice per group.

 
Bone marrow cell-PDGF synergism in restoration of cardiac allograft function. In an attempt to reverse the impairment of cardiac allograft function imparted by alterations in the diabetic vasculature, including bone marrow-derived cells, the diabetic mice were transplanted with bone marrow cells isolated from healthy control animals. Transplantation of these cells did not reverse the diabetic delay in allograft function (Fig. 3). The combination of control bone marrow cell transplantation and pinnal PDGF-AB pretreatment did, however, reverse the PDGF-AB-induced impairment in allograft activity.

To probe the potential mechanisms mediating the synergistic restoration of cardiac angiogenic function, the tissue distribution of transplanted cells with and without PDGF-AB pretreatment of the diabetic tissue was examined. This histological analysis demonstrated significantly greater numbers of wild-type, donor-derived cells populating the diabetic bone marrow compared with transplants into control mice (Fig. 4). Treatment of both control and diabetic mice with PDGF-AB resulted in increased donor-derived cells in the host bone marrow. Moreover, the pinnal pretreatment with PDGF-AB resulted in an alteration in the bone marrow patterning of the donor cells with a sinusoid distribution of transplanted donor cells in the host marrow that was not observed in the control mice or the diabetic host receiving bone marrow alone. There was no significant homing of the transplanted bone marrow cells to the cardiac allografts in either the intact control or diabetic mice. Similarly, control mice treated with PDGF-AB and labeled bone marrow cells did not reveal significant recruitment into the transplanted cardiac allografts. In the mice receiving both wild-type bone marrow and pinnal PDGF-AB pretreatment, histology confirmed the cardiac recruitment of the transplanted bone marrow-derived EPCs, which costained for vWF.


Figure 4
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  		Fig. 4. Assessment of relative tissue density of transplanted donor cells derived from CTL BM in a diabetic host with or without PDGF-AB pretreatment. A: representative micrographs 7 days after cardiac allograft transplantation in host mice administered Rosa control bone marrow-derived cells. X-gal stains of host femur and pinnal cardiac allografts in CTL or DM hosts, with and without coadministration of pinnal PDGF-AB pretreatment. Arrows show donor cells within transplanted cardiac allografts in animals receiving PDGF-AB 24 h before transplantation. B: quantification of number of transplanted beta-Gal(+) Rosa-derived control cells in host femur, pinnae, and cardiac allograft scored per x40 HPF. *P < 0.05 vs. control; **P < 0.05 vs. CTL, DM, and CTL+PDGF-AB. C: representative panels of von Willebrand factor immunostaining (diaminobenzidine) and donor-derived cells (X-gal) costaining in a perivascular distribution (arrows, en face microvascular staining) of pinnal cardiac allografts in diabetic mice.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The present in vivo studies reveal the important combined role of bone marrow-derived cell dysregulation and altered vascular function in the impairment in cardiac angiogenic function observed in diabetic mice. Specifically, these studies demonstrate a primary defect in the ability of cells derived from diabetic bone marrow cells to promote cardiac vascularization with resultant decreases in allogenic cardiac tissue activity. Moreover, the diabetic milieu impairs the in vivo angiogenic function of PDGF-AB pathways and similarly suppresses the cardiac recruitment of bone marrow-derived cells, including EPCs, derived from transplanted control bone marrow. Importantly, the combination of control bone marrow with pinnal PDGF-AB-pretreatment results in improvement in the cardiac angiogenic potential of the transplanted bone marrow cells and promotes the survival of transplanted cardiac tissue.

The STZ treatment mice provided a quantitative approach to study the impairment as well as potential improvement in cardiac angiogenic function in diabetic mice. To this end, the failure of the diabetic bone marrow cells to restore vascularization of the cardiac allografts in the older mice may parallel the dysfunction of cells derived from the aging bone marrow. Indeed, diabetes has been suggested to be a model of vascular aging (25, 26), with accumulated effects of changes such as oxidative stress, altered signaling pathways, and advanced glycation end products that may contribute to the impairment in both local endothelial cell- and EPC-mediated angiogenic function (7, 8). However, the failure of the control bone marrow to fully restore cardiac vascular function suggests that the diabetic changes may be more extensive than those observed with physiological aging.

The deleterious effects of PDGF-AB treatment on cardiac allograft function in the diabetic hosts demonstrate the importance of local shifts in diabetic vascular function that differ significantly from age-related physiological changes. In the nondiabetic state, PDGF-AB enhances angiogenesis and promotes the function of the cardiac allografts in young (6) as well as older mice (7, 29). PDGF-AB pretreatment of the diabetic pinnal tissue, however, resulted in an impairment in cardiac allograft function, suggesting that the signaling pathways and/or downstream proangiogenic cascades induced by PDGF-AB are dysfunctional in the local diabetic vascular milieu. To this end, previous studies (7, 8, 29) have established the interrelationship between PDGF-AB- and EPC-mediated angiogenic function involving the induction of PDGF receptors to promote cardiac angiogenesis and cardioprotection in rodent model systems. Moreover, in addition to potential changes involving peripheral endothelial cells and circulating EPCs, the actions of PDGF on other vascular cell targets, including pericytes and smooth muscle cells (11), may result in the compromise of the transplanted cardiac tissue.

The beneficial synergism of wild-type bone marrow and PDGF-AB demonstrates the importance of local and systemic pathways in diabetic vascular impairment. Our studies utilizing bone marrow-derived cells from nondiabetic mice reveal that bone marrow-derived cells, such as vWF+EPCs, are a target of local PDGF-AB pathways in cardiac angiogenesis, with the impairment in the diabetic EPCs potentially underlying the loss of PDGF-AB-mediated cardiac angiogenic function. Indeed, the capacity of wild-type bone marrow cells to restore the cardioprotective effects of PDGF-AB in the diabetic pinnal allografts demonstrates the importance of bone marrow-peripheral vascular interactions in the regulation of local vascular function. Mechanistically, such regulation may parallel the autocrine and paracrine pathways of EPCs that can govern PDGF-AB induction in senescent cardiac angiogenesis (6, 7, 29) and stem cell differentiation in bone marrow-mediated cardiogenesis (28). Moreover, the induced sinusoidal distribution of the donor cells in the diabetic bone marrow after pinnal PDGF-AB pretreatment suggests that the interaction between the wild-type bone marrow-derived cells, including EPCs, and PDGF-AB in the pinnal vasculature may induce positive feedback loops to the chimeric bone marrow induced by local angiogenic pathways. Indeed, the increased density of donor-derived cells in the bone marrow of control mice treated with PDGF-AB demonstrates the importance of peripheral growth factor pathways in bone marrow function. To this end, previous studies have demonstrated that PDGF-AB can expand populations of CD34+ progenitor cells in vitro (21), which have been shown to promote vascularization of ischemic hindlimbs after injection into diabetic models (16). These findings suggest that PDGF-AB may alter the function of the EPCs after recruitment to the angiogenic foci, potentially inducing systemic growth factors such as stromal cell-derived factor 1 or vascular endothelial growth factor and/or the potential rehoming of the peripherally stimulated EPCs to the bone marrow to promote the recruitment of additional cells to synergize with the local vasculature to enhance cardiac angiogenesis in the diabetic milieu.

The synergism between systemic, bone marrow cell-mediated function and PDGF-AB pathways may provide significant cardioprotection for the diabetic heart. The local and systemic actions of PDGF-AB to enhance EPC migration in the microvasculature as well as the bone marrow, respectively, suggest this synergism will improve function in other vascular beds, including the microvascular circulation, to potentially reverse the diabetic impairment in wound healing. Further studies to more fully define the mechanisms mediating the interactions between bone marrow-derived and local vascular cells, in the peripheral vasculature as well as the endogenous bone marrow, may facilitate the development of novel approaches to decrease the impact of diabetes on cardiac and vascular diseases.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This research was supported by an American Heart Association Heritage Research Fellowship (to D. A. Klibansky) and National Institutes of Health Grants AG-20320, AG-20918, and HL-67839 (to J. M. Edelberg).


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. M. Edelberg, Weill Medical College, 525 East 68 Str., New York, NY 10021 (e-mail: jme2002{at}med.cornell.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 DISCUSSION
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 REFERENCES
 

  1. Abaci A, Oguzhan A, Eryol NK, and Ergin A. Effect of potential confounding factors on the thrombolysis in myocardial infarction (TIMI) trial frame count and its reproducibility. Circulation 100: 2219–2223, 1999.[Abstract/Free Full Text]
  2. Alexander CM, Landsman PB, and Teutsch SM. Diabetes mellitus, impaired fasting glucose, atherosclerotic risk factors, and prevalence of coronary heart disease. Am J Cardiol 86: 897–902, 2000.[CrossRef][ISI][Medline]
  3. Brownlee M. Advanced protein glycosylation in diabetes and aging. Annu Rev Med 46: 223–234, 1995.[CrossRef][ISI][Medline]
  4. Brownlee M, Vlassara H, and Cerami A. Nonenzymatic glycosylation and the pathogenesis of diabetic complications. Ann Intern Med 101: 527–537, 1984.[ISI][Medline]
  5. Bucala R, Tracey KJ, and Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest 87: 432–438, 1991.[ISI][Medline]
  6. Edelberg JM, Jacobson JT, Gidseg DS, Tang L, and Christini DJ. Enhanced myocyte-based biosensing of the blood-borne signals regulating chronotropy. J Appl Physiol 92: 581–585, 2002.[Abstract/Free Full Text]
  7. Edelberg JM, Lee SH, Kaur M, Tang L, Feirt NM, McCabe S, Bramwell O, Wong SC, and Hong MK. Platelet-derived growth factor-AB limits the extent of myocardial infarction in a rat model: feasibility of restoring impaired angiogenic capacity in the aging heart. Circulation 105: 608–613, 2002.[Abstract/Free Full Text]
  8. Edelberg JM, Tang L, Hattori K, Lyden D, and Rafii S. Young adult bone marrow-derived endothelial precursor cells restore aging-impaired cardiac angiogenic function. Circ Res 90: E89–E93, 2002.
  9. Garcia MJ, McNamara PM, Gordon T, and Kannel WB. Morbidity and mortality in diabetics in the Framingham population. Sixteen year follow-up study. Diabetes 23: 105–111, 1974.[ISI][Medline]
  10. Hamuro M, Polan J, Natarajan M, and Mohan S. High glucose induced nuclear factor kappa B mediated inhibition of endothelial cell migration. Atherosclerosis 162: 277–287, 2002.[CrossRef][ISI][Medline]
  11. Heldin CH and Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79: 1283–1316, 1999.[Abstract/Free Full Text]
  12. Hogikyan RV, Galecki AT, Pitt B, Halter JB, Greene DA, and Supiano MA. Specific impairment of endothelium-dependent vasodilation in subjects with Type 2 diabetes independent of obesity. J Clin Endocrinol Metab 83: 1946–1952, 1998.[Abstract/Free Full Text]
  13. Jeppesen J, Hein HO, Suadicani P, and Gyntelberg F. Relation of high TG-low HDL cholesterol and LDL cholesterol to the incidence of ischemic heart disease. An 8-year follow-up in the Copenhagen Male Study. Arterioscler Thromb Vasc Biol 17: 1114–1120, 1997.[Abstract/Free Full Text]
  14. Like AA and Rossini AA. Streptozotocin-induced pancreatic insulitis: new model of diabetes mellitus. Science 193: 415–417, 1976.[Abstract/Free Full Text]
  15. Loomans CJ, de Koning EJ, Staal FJ, Rookmaaker MB, Verseyden C, de Boer HC, Verhaar MC, Braam B, Rabelink TJ, and van Zonneveld AJ. Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of Type 1 diabetes. Diabetes 53: 195–199, 2004.[Abstract/Free Full Text]
  16. Schatteman GC, Hanlon HD, Jiao C, Dodds SG, and Christy BA. Blood-derived angioblasts accelerate blood-flow restoration in diabetic mice. J Clin Invest 106: 571–578, 2000.[ISI][Medline]
  17. Schleicher ED, Wagner E, and Nerlich AG. Increased accumulation of the glycoxidation product N{epsilon}-(carboxymethyl)lysine in human tissues in diabetes and aging. J Clin Invest 99: 457–468, 1997.[ISI][Medline]
  18. Schmidt AM, Yan SD, Wautier JL, and Stern D. Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Circ Res 84: 489–497, 1999.[Abstract/Free Full Text]
  19. Sivan-Loukianova E, Awad OA, Stepanovic V, Bickenbach J, and Schatteman GC. CD34+ blood cells accelerate vascularization and healing of diabetic mouse skin wounds. J Vasc Res 40: 368–377, 2003.[CrossRef][ISI][Medline]
  20. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, and Holman RR. Association of glycaemia with macrovascular and microvascular complications of Type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321: 405–412, 2000.[Abstract/Free Full Text]
  21. Su RJ, Zhang XB, Li K, Yang M, Li CK, Fok TF, James AE, Pong H, and Yuen PM. Platelet-derived growth factor promotes ex vivo expansion of CD34+ cells from human cord blood and enhances long-term culture-initiating cells, non-obese diabetic/severe combined immunodeficient repopulating cells and formation of adherent cells. Br J Haematol 117: 735–746, 2002.[CrossRef][ISI][Medline]
  22. Tamarat R, Silvestre JS, Le Ricousse-Roussanne S, Barateau V, Lecomte-Raclet L, Clergue M, Duriez M, Tobelem G, and Levy BI. Impairment in ischemia-induced neovascularization in diabetes: bone marrow mononuclear cell dysfunction and therapeutic potential of placenta growth factor treatment. Am J Pathol 164: 457–466, 2004.[Abstract/Free Full Text]
  23. Tepper OM, Galiano RD, Capla JM, Kalka C, Gagne PJ, Jacobowitz GR, Levine JP, and Gurtner GC. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation 106: 2781–2786, 2002.[Abstract/Free Full Text]
  24. Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, Zeiher AM, and Dimmeler S. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 89: E1–E7, 2001.[ISI][Medline]
  25. Vlassara H, Fuh H, Makita Z, Krungkrai S, Cerami A, and Bucala R. Exogenous advanced glycosylation end products induce complex vascular dysfunction in normal animals: a model for diabetic and aging complications. Proc Natl Acad Sci USA 89: 12043–12047, 1992.[Abstract/Free Full Text]
  26. Vlassara H, Valinsky J, Brownlee M, Cerami C, Nishimoto S, and Cerami A. Advanced glycosylation endproducts on erythrocyte cell surface induce receptor-mediated phagocytosis by macrophages. A model for turnover of aging cells. J Exp Med 166: 539–549, 1987.[Abstract/Free Full Text]
  27. Williams SB, Cusco JA, Roddy MA, Johnstone MT, and Creager MA. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 27: 567–574, 1996.[Abstract]
  28. Xaymardan M, Tang L, Zagreda L, Pallante B, Zheng J, Chazen JL, Chin A, Duignan I, Nahirney P, Rafii S, Mikawa T, and Edelberg JM. Platelet-derived growth factor-AB promotes the generation of adult bone marrow-derived cardiac myocytes. Circ Res 94: E39–E45, 2004.
  29. Xaymardan M, Zheng J, Duignan I, Chin A, Holm JM, Ballard VL, and Edelberg JM. Senescent impairment in synergistic cytokine pathways that provide rapid cardioprotection in the rat heart. J Exp Med 199: 797–804, 2004.[Abstract/Free Full Text]
  30. Yarom R, Zirkin H, Stammler G, and Rose AG. Human coronary microvessels in diabetes and ischaemia. Morphometric study of autopsy material. J Pathol 166: 265–270, 1992.[CrossRef][ISI][Medline]
  31. Zhang L, Zalewski A, Liu Y, Mazurek T, Cowan S, Martin JL, Hofmann SM, Vlassara H, and Shi Y. Diabetes-induced oxidative stress and low-grade inflammation in porcine coronary arteries. Circulation 108: 472–478, 2003.[Abstract/Free Full Text]



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V. L.T. Ballard and J. M. Edelberg
Stem Cells and the Regeneration of the Aging Cardiovascular System
Circ. Res., April 27, 2007; 100(8): 1116 - 1127.
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00652.2005v1
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