EXPERIMENTAL STUDY
Effect of human recombinant vascular endothelial growth factor165 on progression of atherosclerotic plaque
Francesca L. Celletti, MDa,
Paul R. Hilfiker, MDa,
Paras Ghafouri, BSa and
Michael D. Dake, MDa
a Department of Cardiovascular and Interventional Radiology, Stanford University Medical Center, Stanford, California, USA
Manuscript received August 11, 2000;
revised manuscript received February 9, 2001,
accepted March 14, 2001.
Reprint requests and correspondence: Dr. Michael D. Dake, Department of Cardiovascular and Interventional Radiology, Room H 3647, Stanford University Medical Center, Stanford, California 94305
mddake{at}stanford.edu
 |
Abstract
|
|---|
OBJECTIVES
This study was designed to evaluate the impact of recombinant human vascular endothelial growth factor165 (rhVEGF) on atherosclerotic plaque progression.
BACKGROUND
Therapeutic angiogenesis represents a promising treatment for ischemic diseases. However, angiogenesis may impact atherosclerosis.
METHODS
Albumin or rhVEGF was administered by a single intramuscular injection (2 µg/kg body weight) to New Zealand White rabbits fed with a 0.25% cholesterol diet beginning three weeks before therapy. Subsets of rabbits from each group underwent perfusion-fixation and harvesting of the thoracic aorta for morphometric and immunohistochemical analyses at 7 or 21 days.
RESULTS
The mean plaque area was 15.75 ± 2.28% and 22.00 ± 3.24% with VEGF and 0.67 ± 0.22% and 1.17 ± 0.34% with albumin at 7 and 21 days, respectively. The plaque circumference was 13.00 ± 2.58% and 23.75 ± 2.86% with VEGF and 2.50 ± 0.65% and 6.25 ± 1.88% with albumin at 7 and 21 days, respectively. The maximal plaque thickness was 0.11 ± 0.002 and 0.15 ± 0.007 mm with VEGF and 0.04 ± 0.009 and 0.07 ± 0.003 mm with albumin at 7 and 21 days, respectively. The endothelial density (reported as percent total plaque area) was 31.75 ± 4.42% and 63.00 ± 8.45% with VEGF and 7.75 ± 1.65% and 12.75 ± 1.93% with albumin at 7 and 21 days, respectively. The macrophage density was 4.5 ± 0.86 and 19.25 ± 1.54 with VEGF and 4.26 ± 0.75 and 6.00 ± 1.08 with albumin at 7 and 21 days, respectively.
CONCLUSIONS
Recombinant human VEGF increases the rate and degree of atherosclerotic plaque formation in the thoracic aorta in a cholesterol-fed rabbit model.
|
Abbreviations and Acronyms
| | IgG | = immunoglobulin G | | rhVEGF | = recombinant human vascular endothelial growth factor165 |
|
Vascular endothelial growth factor (VEGF), a multifunctional cytokine for endothelial cells expressing VEGF receptor-1 (flt-1) and 2 (flk-1/KDR) (1–3), can increase the development of collateral arteries. Thus, it has become an exciting new therapeutic agent for vascular diseases (4).
Although it is relatively endothelial cell-specific, VEGF also affects monocyte activation and migration through a primary effect on receptor flt-1 in bone marrow and peripheral blood (5–8). Macrophages, in turn, contribute to angiogenesis by production of factors such as VEGF, tumor
necrosis factor-alpha and thymidine phosphorylases (9). In addition, macrophages, the most numerous inflammatory cells present in the atherosclerotic lesion, also elaborate growth factors and cytokines, which play a central role in atherogenesis (9–12).
Preclinical and clinical studies indicate that angiogenic growth factors can stimulate the development of collateral vessels (4). However, recent studies have suggested that angiogenesis may also be necessary for plaque progression (13).
Based on these studies and on the described effects of VEGF on endothelial cells and macrophages, we evaluated the impact of remote administration of rhVEGF on progression of atherosclerotic plaque in the thoracic aorta of cholesterol-fed rabbits.
|
Methods
|
|---|
Animals and experimental design.
Albumin or rhVEGF was administered by a single intramuscular injection (2 µg/kg body weight) to 16 New Zealand White male rabbits (3.00 to 3.2 kg) fed with a 0.25% cholesterol diet beginning 21 days before treatment. This animal model was selected because a large body of previous work demonstrated consistent formation of arterial plaques, with a composition and morphology resembling human lesions (14,15). The dose of rhVEGF was selected because it is one of the lowest dose regimens previously shown to be therapeutic in any animal model (16).
At 7 and 21 days after treatment, four rabbits each underwent total body perfusion fixation. Then, the thoracic aorta, from the aortic root to the diaphragm, was harvested and post-fixed in 10% neutral buffered formalin for 12 h before undergoing morphometric analysis, as described subsequently.
Plaque morphometric evaluation.
All observers were blinded to the treatment groups and time points for analyses. The arteries were divided into four equal segments, with all sections obtained proximally. Eighty sections (5 to 8 µm in thickness, 20 each for 4 segments), from the aortic root to the mid-portion of the descending thoracic aorta, were prepared. The slides were stained with Verhoeff reagent and hematoxylin. The plaque images were analyzed with the Image Pro plus system (Media Cybernetics, Silver Spring, Maryland). Plaque area, circumference and thickness were evaluated. Plaque area was calculated as the difference between the luminal area and the area delimited by the internal elastic lamina. The results were normalized to total vessel cross-sectional area for each arterial section to eliminate variations due solely to vessel size.
Plaque circumference was evaluated by the ratio of the extension of the cross-sectional circumference of each plaque traced manually to the total luminal circumference. Finally, maximal thickness of the plaque for each axial section was measured.
Immunohistochemistry.
Endothelial area
Six cross-sections (5 µm in thickness) from each animal, two each from the first three segments, were incubated overnight with a primary monoclonal CD31 antibody (20 µg/ml; Pharmingen, San Diego, California). After washing, the slides were incubated with biotinylated anti-mouse immunoglobulin G (IgG) (1:250 dilution; Calbiochem-Novabiochem, La Jolla, California) and then with an avidin-biotin peroxidase complex (Vector Laboratories, Burlingame, California). For all immunohistochemistry studies, the sections incubated with diluent and isotype-matched antibody served as separate negative control samples. The images were analyzed in a blinded manner to determine the total number of positive pixels, with the results normalized to total plaque area to eliminate error due simply to differences in plaque size. This method was selected in lieu of the more traditional lumen-count capillary density to evaluate forming vessels quantitatively, without errors caused by variable microvessel compression and fixation or observer bias.
Macrophages
Six cross sections (5 µm in thickness), as described earlier, were incubated overnight with primary monoclonal antibody to rabbit macrophages (clone RAM-11, 1:800 dilution, Dako, Carpinteria, California). After washing, the slides were incubated with biotinylated anti-mouse IgG (Calbiochem, San Diego, California) and then with an avidin-biotin peroxidase complex (Pierce, Rockford, Illinois). The total number of positive cells was manually counted for each cross section by an observer in a blinded manner.
Statistical analysis.
Data are expressed as the mean value ± SE. Statistical significance for these analyses was determined by two-way analysis of variance (ANOVA; time vs. treatment group) and by one-way repeated measures ANOVA (for each group at each time point), with significance determined at 95% (Fisher, Bonferroni, Tukey-A, Student-Newman-Keuls post hoc testing performed where applicable using Statview or SPSS version 6.1).
|
Results
|
|---|
Plaque morphometry.
Plaque area
As detailed in Table 1, the mean plaque area is significantly increased compared with that of control samples at both 7 and 21 days after VEGF administration
View this table:
[in this window]
[in a new window]
|
Table 1 Percentage of Total Cross Section Represented by Plaque Area (Difference Between Lumen Area and Area Delimited by Internal Elastic Lamina) at Either 7 or 21 Days After Treatment with rhVEGF (2 µg/kg by a Single Intramuscular Injection) or Albumin
|
|
Plaque circumference
As detailed in Table 2, circumferential plaque extension is significantly greater compared with that of control samples both at 7 and 21 days after VEGF administration
View this table:
[in this window]
[in a new window]
|
Table 2 Percentage of Total Lumen Circumference Represented by Plaque at Either 7 or 21 Days After Treatment With rhVEGF (2 µg/kg by a Single Intramuscular Injection) or Albumin
|
|
Plaque thickness
Maximal plaque thickness (Table 3) is significantly increased compared with that of control samples at both 7 and 21 days after VEGF administration.
View this table:
[in this window]
[in a new window]
|
Table 3 Maximal Plaque Thickness (mm) Was Determined for Cross Sections Obtained at Either 7 or 21 Days After Treatment With rhVEGF (2 µg/kg by a Single Intramuscular Injection) or Albumin
|
|
Figures 1 and 2are representative photomicrographs of Verhoeff -van Gieson/Masson sections depicting an increased degree of atherosclerosis in the VEGF-treated groups.
View larger version (50K):
[in this window]
[in a new window]
|
Figure 1 Representative photomicrographs at seven days. Low-magnification (x8, before 50% reduction) photographs of thoracic aortic cross sections stained with Verhoeff and counterstained with hematoxylin from (A) a rabbit treated with rhVEGF (2 µg/kg by a single intramuscular injection) and (B) an albumin-treated rabbit.
|
|
View larger version (59K):
[in this window]
[in a new window]
|
Figure 2 Representative photomicrographs at 21 days. Low-magnification (x8, before 50% reduction) photographs of thoracic aortic cross sections stained with Verhoeff and counterstained with hematoxylin from (A) a rabbit treated with rhVEGF (2 µg/kg by a single intramuscular injection) and (B) an albumin-treated rabbit.
|
|
Immunohistochemistry.
Endothelial cells
As detailed in Table 4, the total CD31 positive area (percent total plaque area) increased significantly compared with that of control samples at both 7 and 21 days after VEGF administration. The total CD31-positive area is presented instead of lumen-count capillary density to evaluate forming vessels quantitatively, without artifactual errors caused by tissue sectioning techniques or observer bias.
View this table:
[in this window]
[in a new window]
|
Table 4 Endothelial-Positive Area: Number of CD31-Positive Cells Normalized to Total Plaque Area (cells/mm2) at Either 7 or 21 Days After Treatment With rhVEGF (2 µg/kg by a Single Intramuscular Injection) or Albumin
|
|
Macrophages
As detailed in Table 5, RAM-11–positive cells per cross section are significantly greater compared with those of control samples at 21 days, but not at 7 days after VEGF administration.
View this table:
[in this window]
[in a new window]
|
Table 5 Macrophage Infiltration: Number of RAM-11–Positive Cells Per Cross Section Obtained at Either 7 or 21 Days After Treatment With rhVEGF (2 µg/kg by a Single Intramuscular Injection) or Albumin
|
|
|
Discussion
|
|---|
These results demonstrate that rhVEGF can induce progression of atherosclerotic plaque, although exogenous endothelial cell growth factors are already present in plaque tissue (13). Complementing these findings, a recent study (13) found that inhibition of angiogenesis successfully limited progression of atherosclerosis.
Plaque progression.
In the present study, rhVEGF increases plaque progression at both 7 and 21 days. In the VEGF-treated group, the mean plaque area at 7 and 21 days was 23- and 18-fold greater, respectively, than that of the control samples. Circumferential plaque extension at 7 and 21 days increased 5.2 and 3.8 times, respectively, over that of control samples. Vascular endothelia growth factor165 potentially impacts plaque formation through complex stimuli, including endothelialization and macrophage infiltration. In fact, VEGF may increase plaque capillary density and extend the depth of neovascularization to the intima (17–19). The clinical importance of plaque neovascularization is suggested by studies that show a higher capillary density in lesions with mural hemorrhage, plaque rupture or unstable angina (19–21). In addition, factors that stimulate plaque angiogenesis may also precipitate plaque rupture, with subsequent myocardial infarction and ischemic stroke (20).
Endothelial density.
Despite increased plaque area, as described earlier, cross sections of the thoracic aorta from the VEGF-treated group showed a 4- to 4.9-fold increases in the endothelial-positive area after 7 and 21 days, respectively. These results suggest increased vascularity of lesions in the rhVEGF group. Previous work suggests that plaque angiogenesis is frequently associated with increased infiltration of macrophages, T cells and mast cells, and ultimately correlates with the degree of luminal stenosis (8–12).
Macrophage infiltration.
Given the potential of VEGF to increase circulating macrophage precursor levels, we quantitatively evaluated local cross-sectional macrophage infiltration. Although all other plaque measurements and cellular variables studied revealed increases at both 7 and 21 days, macrophage infiltration significantly increased in the rhVEGF-treated group only at 21 days (3.2-fold). A number of factors may be involved in this apparent delay in macrophage accumulation relative to all other variables. Less mature macrophages may accumulate earlier and differentiate over time (i.e., not RAM-11–positive initially), or mature macrophages may actually exhibit delayed tissue accumulation. Furthermore, immunohistochemical studies must be undertaken to better assess the relative contribution of each. However, these findings are consistent with previous observations that VEGF affects monocyte activation and migration through a primary effect on receptor flt-1 in bone marrow and peripheral blood (5–7). In this regard, an enhanced understanding of these observations is crucially important because macrophages elaborate growth factors and cytokines that mediate intimal hyperplasia and may, therefore, mediate atherogenesis (8,9,11,12). Macrophages may also contribute to plaque progression through elaboration of a variety of tissue factors, such as matrix metalloproteinases and other hydrolytic enzymes (22). In addition, monocytes are known to sustain proliferation of monocytes, smooth muscle and endothelial cells (8–11).
Study implications.
Recently, it was clinically shown that intra-arterial administration of rhVEGF markedly increases the development of collateral vessels in patients with ischemic syndromes. As a result, VEGF has become a potentially exciting new therapeutic agent for coronary and peripheral occlusive vascular diseases (4). However, it has been reported that in vivo introduction of human VEGF165 complementary deoxyribonucleic acid into rabbit carotid arteries by Sendai virus liposomes induces prominent angiomatoid proliferation of enothelial cells and thickening of the intima (23) and that VEGF administration exacerbates neointimal thickening after vascular injury in dogs (24). Consistent with these and other recent studies (25), we have shown that even a modest dose of rhVEGF can enhance progression of atherosclerotic plaques in vivo. Although additional studies are required to better characterize the mechanisms underlying this observation, this study suggests that alternate dosing regimens or delivery strategies must be considered. In addition to evaluating new ways to deliver the drug (i.e., local delivery) to avoid systemic effects, new ways to locally block the impact of VEGF on undesirable pathways may need to be developed.
|
Footnotes
|
|---|
This work was funded through departmental resources.
|
References
|
|---|
1. Connolly DT, Heuvelman DM, Nelson R, et al. Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest. 1989;84:1470–1478[Medline]
2. Keck PJ, Hauser SD, Krivi G, et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989;246:1309–1312[Abstract/Free Full Text]
3. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246:1306–1309[Abstract/Free Full Text]
4. Isner JM, Asahara T. Angiogenesis and vasculogenesis as therapeutic strategies for postnatal neovascularization. J Clin Invest. 1999;103:1231–1236[Medline]
5. Shen H, Clauss M, Ryan J, et al. Characterization of vascular permeability factor/vascular endothelial growth factor receptors on mononuclear phagocytes. Blood. 1993;81:2767–2773[Abstract/Free Full Text]
6. Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marme D. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the receptor flt-1. Blood. 1996;87:3336–3343[Abstract/Free Full Text]
7. Clauss M, Gerlach M, Geralch H, et al. Vascular permeability factor: a tumor-derived polypeptyde that induces endothelial cells and monocyte procoagulant activity, and promotes monocyte migration. J Exp Med. 1990;172:1535–1545[Abstract/Free Full Text]
8. Leek RD, Hunt NC, Landers RJ, Lewis CE, Royds JA, Harris AL. Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer. J Pathol. 2000;190:430–436[CrossRef][Medline]
9. Ross R. Localization of PDGF-B protein in macrophages in all phases of atherogenesis. Science. 1990;248:1009–1012[Abstract/Free Full Text]
10. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801–809[CrossRef][Medline]
11. Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis. 1986;6:131–138[Abstract/Free Full Text]
12. Polverini PJ, Cotran RS, Gimbrone MA Jr, Unanue ER. Activated macrophages induce vascular proliferation. Nature. 1977;269:804–806[CrossRef][Medline]
13. Moulton KS, Heller E, Konerding MA, Flynn E, Palinski W, Folkman J. Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. Circulation. 1999;99:1726–1732[Abstract/Free Full Text]
14. Kolodgie FD, Katocs AS, Largis EE, et al. Hypercholesterolemia in the rabbit induced by feeding graded amounts of low-level cholesterol. Artereioscler Thromb Vasc Biol. 1996;16:1454–1464
15. Kratky RG, Ivey J, Rogers KA. The distribution of fibro-fatty atherosclerotic lesions in the aortae of casein- and cholesterol-fed rabbits. Atherosclerosis. 1993;1:121–131
16. Lopez JJ, Laham RJ, Stamler A, et al. VEGF administration in chronic myocardial ischemia in pigs. Cardiovasc Res. 1998;40:272–281[Abstract/Free Full Text]
17. Gown AM, Tsukada T, Ross R. Human atherosclerosis: II. Immunocytochemical analysis of the cellular composition of human atherosclerotic lesions. Am J Pathol. 1986;125:191–197[Abstract]
18. Patterson JC. Capillary rupture with intimal hemorrhage as a causative factor in coronary thrombosis. Arch Pathol. 1938;25:323–329
19. Tenaglia AN, Peters KG, Sketch MH, Annex BH. Neovascularization in atherectomy specimens in patients with unstable angina. Am Heart J. 1998;135:10–14[CrossRef][Medline]
20. O’Brien ER, Garvin MR, Dev R, et al. Angiogenesis in human coronary atherosclerotic plaques. Am J Pathol. 1993;143:164–172[Abstract]
21. Libby P, Ordovas JM, Auger KR, Robbins AH, Birinyi LK, Dinarello CA. Endotoxin and tumor necrosis factor induce interleukin-1 gene expression in adult human vascular endothelial cells. Am J Pathol. 1986;124:179–185[Abstract]
22. Jopnes JI, Prevette T, Gockeran A. Ligand occupancy of the alpha-V-beta-3 integrin is necessary for smooth muscle cells to migrate in response to insulin-like growth factor. Proc Natl Acad Sci USA. 1997;94:9308–9313[Abstract/Free Full Text]
23. Yonemitsu Y, Kaneda Y, Morishita R, Nakagawa K, Nakashima Y, Sueshi K. Characterization of in vivo gene transfer into the arterial wall mediated by the Sendai virus (hemagglutinin virus of Japan) liposomes: an effective tool for the in vivo study of arterial diseases. Lab Invest. 1996;75:313–323[Medline]
24. Lazarous DF, Shou M, Scheinowit M, et al. Comparative effects of basic fibroblast growth factor and vascular endothelial growth factor on coronary collateral development and the arterial response to injury. Circulation. 1996;94:1074–1082[Abstract/Free Full Text]
25. Lee RJ, Springer ML, Blanco-Bose WE, Shaw R, Ursell P, Blau HM. VEGF gene delivery to myocardium: deleterious effects of unregulated expression. Circulation. 2000;102:898–901[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
Q. Hao, L. Wang, and H. Tang
Vascular endothelial growth factor induces protein kinase D-dependent production of proinflammatory cytokines in endothelial cells
Am J Physiol Cell Physiol,
April 1, 2009;
296(4):
C821 - C827.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. C.A. Stene, R. Frikke-Schmidt, B. G. Nordestgaard, P. Grande, P. Schnohr, and A. Tybjaerg-Hansen
Functional Promoter Variant in Zinc Finger Protein 202 Predicts Severe Atherosclerosis and Ischemic Heart Disease
J. Am. Coll. Cardiol.,
July 29, 2008;
52(5):
369 - 377.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Rega, C. Kaun, S. Demyanets, S. Pfaffenberger, K. Rychli, P.J. Hohensinner, S.P. Kastl, W.S. Speidl, T.W. Weiss, J.M. Breuss, et al.
Vascular Endothelial Growth Factor Is Induced by the Inflammatory Cytokines Interleukin-6 and Oncostatin M in Human Adipose Tissue In Vitro and in Murine Adipose Tissue In Vivo
Arterioscler. Thromb. Vasc. Biol.,
July 1, 2007;
27(7):
1587 - 1595.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Doyle and N. Caplice
Plaque Neovascularization and Antiangiogenic Therapy for Atherosclerosis
J. Am. Coll. Cardiol.,
May 29, 2007;
49(21):
2073 - 2080.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K.-Y. Chyu and P. K. Shah
Choking off Plaque Neovascularity: A Promising Atheroprotective Strategy or A Double-Edged Sword?
Arterioscler. Thromb. Vasc. Biol.,
May 1, 2007;
27(5):
993 - 995.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Anwaruddin, A. T. Askari, and E. J. Topol
Redefining Risk in Acute Coronary Syndromes Using Molecular Medicine
J. Am. Coll. Cardiol.,
January 23, 2007;
49(3):
279 - 289.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Kronzon and P. A. Tunick
Aortic Atherosclerotic Disease and Stroke
Circulation,
July 4, 2006;
114(1):
63 - 75.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Dulak, S. P Schwarzacher, R. H Zwick, H. Alber, G. Millonig, C. Weiss, H. Hugel, M. Frick, A. Jozkowicz, O. Pachinger, et al.
Effects of local gene transfer of VEGF on neointima formation after balloon injury in hypercholesterolemic rabbits
Vascular Medicine,
November 1, 2005;
10(4):
285 - 291.
[Abstract]
[PDF]
|
|
|
|
|
|
|
Y. Tsutsumi and D. W. Losordo
Double Face of VEGF
Circulation,
August 30, 2005;
112(9):
1248 - 1250.
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Suda, L. A. Smith, L. V. d'Uscio, T. E. Peterson, and Z. S. Katusic
In Vivo Expression of Recombinant Vascular Endothelial Growth Factor in Rabbit Carotid Artery Increases Production of Superoxide Anion
Arterioscler. Thromb. Vasc. Biol.,
March 1, 2005;
25(3):
506 - 511.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Coats and R. Wadsworth
Marriage of resistance and conduit arteries breeds critical limb ischemia
Am J Physiol Heart Circ Physiol,
March 1, 2005;
288(3):
H1044 - H1050.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Rodriguez, B. Nespereira, M. Perez-Ilzarbe, E. Eguinoa, and J. A. Paramo
Vitamins C and E prevent endothelial VEGF and VEGFR-2 overexpression induced by porcine hypercholesterolemic LDL
Cardiovasc Res,
February 15, 2005;
65(3):
665 - 673.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D.-H. Kang, E. S. Yu, K.-I. Yoon, and R. Johnson
The Impact of Gender on Progression of Renal Disease: Potential Role of Estrogen-Mediated Vascular Endothelial Growth Factor Regulation and Vascular Protection
Am. J. Pathol.,
February 1, 2004;
164(2):
679 - 688.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Pels, C. Deiner, S. E Coupland, M. Noutsias, A. P Sutter, H.-P. Schultheiss, S. Yla-Herttuala, and P. L Schwimmbeck
Effect of adventitial VEGF165 gene transfer on vascular thickening after coronary artery balloon injury
Cardiovasc Res,
December 1, 2003;
60(3):
664 - 672.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. G. Seipelt, C. L. Backer, C. Mavroudis, V. Stellmach, I. M. Seipelt, M. Cornwell, J. Hernandez, and S. E. Crawford
Topical VEGF Enhances Healing of Thoracic Aortic Anastomosis for Coarctation in a Rabbit Model
Circulation,
September 9, 2003;
108(90101):
II-150 - 154.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Santos, V. I. Peinado, J. Ramirez, J. Morales-Blanhir, R. Bastos, J. Roca, R. Rodriguez-Roisin, and J. A. Barbera
Enhanced Expression of Vascular Endothelial Growth Factor in Pulmonary Arteries of Smokers and Patients with Moderate Chronic Obstructive Pulmonary Disease
Am. J. Respir. Crit. Care Med.,
May 1, 2003;
167(9):
1250 - 1256.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Dulak, A. Jozkowicz, M. Frick, H. F. Alber, W. Dichtl, S. P. Schwarzacher, O. Pachinger, and F. Weidinger
Vascular endothelial growth factor: angiogenesis, atherogenesis or both?
J. Am. Coll. Cardiol.,
December 1, 2001;
38(7):
2137 - 2138.
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. W. Losordo and J. M. Isner
Vascular endothelial growth factor-induced angiogenesis: crouching tiger or hidden dragon?
J. Am. Coll. Cardiol.,
June 15, 2001;
37(8):
2131 - 2135.
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Chen, D. Li, T. Saldeen, and J. L. Mehta
Transforming Growth Factor-{beta}1 Modulates Oxidatively Modified LDL-Induced Expression of Adhesion Molecules: Role of LOX-1
Circ. Res.,
December 7, 2001;
89(12):
1155 - 1160.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods