(Circulation. 1999;99:3188-3198.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Impaired Collateral Vessel Development Associated With Reduced Expression of Vascular Endothelial Growth Factor in ApoE-/- Mice
From the Departments of Medicine (Cardiology) and Biomedical Research, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass, and the Department of Medicine (Cardiology), Duke University, Durham, NC (B.A., K.P.).
Correspondence to Jeffrey M. Isner, MD, St Elizabeth's Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail jisner{at}opal.tufts.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—The impact of disordered lipid metabolism on collateral vessel development was studied in apolipoprotein (apo)E-/- mice with unilateral hindlimb ischemia.
Methods and Results—Hindlimb blood flow and capillary density were markedly reduced in apoE-/- mice versus C57 controls. This was associated with reduced expression of vascular endothelial growth factor (VEGF) in the ischemic limbs of apoE-/- mice. Cell-specific immunostaining localized VEGF protein expression to skeletal myocytes and infiltrating T cells in the ischemic limbs of C57 mice; in contrast, T-cell infiltrates in ischemic limbs of apoE-/- mice were severely reduced. The critical contribution of T cells to VEGF expression and collateral vessel growth was reinforced by the finding of accelerated limb necrosis in athymic nude mice with operatively induced hindlimb ischemia. Adenoviral VEGF gene transfer to apoE-/- mice resulted in marked augmentation of hindlimb blood flow and capillary density.
Conclusions—These findings thus underscore the extent to which hyperlipidemia adversely affects native collateral development but does not preclude augmented collateral vessel growth in response to exogenous cytokines. Moreover, results obtained in the apoE-/- and athymic nude mice imply a critical role for infiltrating T cells as a source of VEGF in neovascularization of ischemic tissues.
Key Words: atherosclerosis • collateral circulation • growth substances • angiogenesis • apolipoproteins
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
We sought to test the hypothesis that disordered lipid metabolism retards collateral vessel growth to ischemic tissues. The apolipoprotein (apo)E-deficient mouse generated by gene targeting1 2 provides an appropriate animal model for such a study. ApoE is a 34-kDa glycoprotein that coats VLDLs, IDLs, and HDLs. It serves as a high-affinity ligand for LDL and putative chylomicron remnant receptors,1 2 thus facilitating the removal of apoE-coated lipoprotein particles from the circulation. In apoE-null (apoE-/-) mice, cholesterol is markedly elevated because of increased levels of VLDLs and IDLs.1 2
In the present series of experiments, we created unilateral hindlimb ischemia in apoE-/- mice and compared the development of collateral vessels in the ischemic limb with that observed in C57 wild-type mice that underwent similar surgery. We observed a marked retardation of collateral vessel development in apoE-/- mice, associated with reduced expression of vascular endothelial growth factor (VEGF) in the ischemic limb. The reduction in endogenous VEGF synthesis appears to result from reduced VEGF expression by skeletal myocytes, as well as a paucity of T-cell infiltrates expressing VEGF. Although hyperlipidemia adversely affected native collateral development, it did not preclude augmented collateral vessel growth in response to supplemental administration of VEGF achieved by adenoviral gene transfer.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Mouse Model of Unilateral Hindlimb Ischemia
Unilateral hindlimb ischemia was induced surgically in each inbred strain as previously described.3 This surgery typically results in oxygen saturations as low as 64% measured at day 0 and myonecrosis in the ischemic hindlimb.3
Laser Doppler Perfusion Imaging
Serial assessment of hindlimb blood flow was performed with a
PIM 1.0 laser Doppler perfusion imager (Lisca) as previously
described.3 4 Calculated perfusion was expressed as a
ratio of left (ischemic) to right (normal) limb.
Previous studies3 established that laser Doppler flow velocity correlated with capillary density in the ischemic limb in C57 mice in which angiogenesis was retarded by administration of neutralizing antibodies prepared against VEGF as well as the angiogenesis inhibitor platelet factor 4 (PF-4). Double immunolabeling for bromodeoxyuridine (BrdU) and CD-31 established that endothelial cell (EC) proliferation peaks at 7 days and is subsequently reduced at days 14 and 21. In mice treated with PF-4 and euthanized 14 days after surgery, capillary density (268±195 versus 1053±371 capillaries/mm2, P<0.01) and EC proliferation (16±29 versus 935±239 BrdU-positive cells/mm2, P<0.01) were significantly reduced in PF-4– versus PBS-injected mice, respectively.
Necropsy Examination
Tissue Preparation
For immunohistochemistry, tissues were fixed in 100%
methanol. A minimum of 3 animals were examined for each time point. For
protein extraction, tissue samples were rinsed in PBS to remove excess
blood, flash-frozen in liquid nitrogen, and stored at -80°C until
used.
Immunohistochemistry
Five-micrometer, paraffin-embedded sections cut
transversely from the mouse hindlimb were used for
immunohistochemistry. ECs were identified with a rat monoclonal
antibody (mAb) against mouse CD-31 (Pharmingen). Staining with CD-31
antibody,5 and in particular this anti-mouse specific CD31
antibody,6 7 has previously been shown to be limited to
capillary endothelium.
VEGF was detected with a rabbit polyclonal antibody (pAb) prepared against human VEGF amino-terminal peptides 1 to 20 (Santa Cruz). The amino-terminal peptides 1 to 20 for mouse and human VEGF are similar except that a Thr (in 11) in the mouse replaces the Ser of the human sequence. This antibody immunoprecipitates a 46-kDa protein (nonreducing conditions) or a 23-kDa protein (reducing conditions) from mouse uterine protein extract corresponding to the size of recombinant human VEGF165 used as a control. Immunoperoxidase staining was performed as before.3 Negative control slides were prepared by substituting preimmune rat serum for the primary mAb or using preabsorption of VEGF Ab with the specific peptide (Santa Cruz).
For measurement of capillary density, tissues were prepared as described by Weidner et al.5 Two different sections were taken 3 mm apart between the knee and ankle. Capillaries were counted per 30 randomly chosen high-power fields (HPFs) on the 2 sections (3 animals per time point). The 30 HPFs (x60) constituted the complete muscle set of the hindlimb. Given the size (in mm2) of the HPFs and the magnification used, the results were calculated as capillaries per square millimeter.
Total leukocytes were identified with anti–CD-45 antibody (Gibco BRL), macrophages with F4/80 antibody (Caltag Labs), and T lymphocytes with anti–CD-3 antibody (Sigma Chemical Co). T cells and macrophages identified by cell-specific immunostains were manually counted in 90 randomly chosen HPFs of sections from the ischemic hindlimb of 3 animals per time point killed at postoperative days 2, 4, 7, and 14.
In Situ Hybridization
In situ hybridization was carried out with the nonradioactive
Genius Labeling and Detection Kit (Boehringer Mannheim) as
previously described.3 Controls included (1) hybridization
with sense probe and (2) use of an irrelevant antibody. Sections were
counterstained with methyl green nucleus–specific stain (Vector).
Immunoprecipitation
Five milligrams of protein pooled equally from diced frozen
hindlimbs of 2 different animals was incubated with VEGF pAb (0.5
µg/mL) (Santa Cruz) or anti–Flk-1 pAb (0.5 µg/mL) (Santa Cruz)
overnight as described previously.3 Positive controls
included recombinant VEGF165 (Genentech).
Negative controls included blotting with an irrelevant antibody.
Experiments were performed in triplicate to ensure
reproducibility.
Fluorescence-Activated Cell Sorting
Analysis
Mononuclear cells were isolated from peripheral
blood with the Ficoll Hypaque system and then washed in PBS. We used
specific anti-mouse antibody (Pharmingen) conjugated with phycoerythrin
(CD-3) or FITC (CD-4 and CD-8). Mononuclear cells were incubated with
anti–CD-3 and CD-4 or anti–CD-3 and CD-8 in medium for 1 hour at
4°C, washed 3 times with cold medium to remove unbound antibody, and
further fixed in 2% paraformaldehyde. After additional
washes, the samples were analyzed with a
fluorescence-activated cell sorting
analyzer.
Intramuscular Adenoviral Transfection
Mice were transfected with E1-deleted recombinant adenovirus
(4x109 pfu in 20% pluronic gel) expressing
either LacZ containing a nuclear localization sequence
nls-LacZ or murine VEGF cDNA. Transfection was performed by
direct intramuscular injection into the ischemic hindlimb with
a 27-gauge needle.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Recovery of Hindlimb Blood Flow Is Retarded in ApoE-/- Mice
In C57 controls (n=10), blood flow was precipitously reduced after surgery (Figure 1
), remained impaired for
7 days, increased to 
55% of the nonischemic limb by day 14,
and ultimately returned to near-normal levels by day 35. A similarly
precipitous reduction in hindlimb blood flow occurred in
apoE-/- mice, but in contrast to C57 mice, flow
recovery was markedly attenuated (n=10). In
apoE-/- mice, a statistically significant
reduction in flow was evident by day 14, persisted at each of the
subsequent time points (21, 28, and 35 days), and never achieved >55%
of that measured for the contralateral normal limb.
|
Capillary Density Is Reduced in ApoE-/- Mice
A precipitous reduction in capillary density was observed in both
strains of mice immediately after surgery (Figure 2) as a result of ischemic
necrosis associated with resection of the femoral artery. By day 4,
capillary restitution in C57 ischemic limbs exceeded that in
apoE-/- mice. A statistically significant
reduction in capillary density per square millimeter of
ischemic tissue was observed at days 4, 7, 14, 21, and 35
(Figure 2). In either strain, vascularity was essentially
limited to apparently viable muscle, as opposed to foci of
fibrosis.
|
Protein extracts from ischemic hindlimb muscles were obtained
at days 4, 7, 14, 21, and 35 after surgery and hybridized with an
antibody against mouse CD-31. Western blot analysis confirmed
that CD-31 (130-kDa) protein was reduced at early time points in
apoE-/- compared with C57 mice (Figure 2
).
Flk-1 Receptor Expression Is Not Reduced Out of Proportion to the
Reduction in CD31-Positive ECs in ApoE-/- Mice
Immunoprecipitation studies indicated that Flk-1
expression was reduced in tissue specimens retrieved from the
ischemic limb of apoE-/- versus control
C57 mice, but only in proportion to the reduced EC population indicated
by Western blot analysis of CD31 in
apoE-/- versus control C57 mice (Figure 3); specifically, temporal expression of
EC Flk-1 protein in ischemic limbs of C57 and
apoE-/- mice corresponded to sequential
recovery of capillary density. Antiphosphotyrosine blot of the Flk-1
immunoprecipitation confirmed that the Flk-1 immunoprecipitate was
functional as early as day 4 in both C57 and
apoE-/- mice, with an increase in
phosphorylation at later time points (data not
shown).
|
VEGF Protein and mRNA Are Reduced in Tissues Retrieved From
Ischemic Limbs of ApoE-/- Mice
We considered that impaired angiogenesis in
apoE-/- mice might be related to reduced
endogenous VEGF. Indeed, development of peak VEGF protein
levels in ischemic limb tissue was both delayed and reduced in
apoE-/- versus control mice (Figure 3).
Tissue specimens harvested from ischemic limbs of
apoE-/- and C57 mice were also
immunostained for VEGF. Consistent with the results
of immunoprecipitation/Western analysis, VEGF was less abundant
in tissue sections from apoE-/- mice compared
with controls. In C57 controls, VEGF immunostaining
could be localized to skeletal myocytes in the ischemic limb
and foci of inflammatory cells. In apoE-/-
mice, VEGF immunostaining of skeletal myocytes was less
abundant (Figure 4). Moreover, we
observed a striking reduction in VEGF immunostaining
contributed by infiltrating inflammatory cells (Figure 4).
Immunostaining of adjacent, serially cut sections for
total leukocytes (anti–CD-45 antibody), macrophages (F4/80
antibody), and T lymphocytes (anti–CD-3 antibody) indicated that the
inflammatory infiltrates in the C57 controls included a large T-cell
population, beginning within 2 days after surgery (1.02±0.02
cells/HPF) and diminishing to background levels by day 14 (0.14±0.02
cells/HPF). In contrast, ischemic tissues harvested at day 2
from apoE-/- mice displayed a marked reduction
in infiltrating T cells (0.20±0.02 cells/HPF, P=0.0021)
(Table, Figure 5).
|
|
|
) in ischemic hindlimbs of C57,
apoE-/-, and nude mice at postoperative day 4. Although a
moderate number of macrophages were seen in all mice, there was
a marked reduction in T-cell infiltrates in apoE vs C57 mice. Cells
marked by arrows as well as unmarked, similar-appearing cells are T
cells; same is true for monocytes and mast cells in other panels.
In situ hybridization using murine
VEGF165-specific digoxigenin-labeled probes was
performed 7 days after surgery. By use of
VEGF165-antisense probe in C57 mice, VEGF mRNA
was detectable in ischemic muscle fibers (Figure 6), which corresponded to
immunostaining for VEGF protein. VEGF mRNA was barely
detectable in legs of control animals that had not undergone surgery
(not shown). In contrast, both VEGF protein and mRNA expression were
markedly reduced in the skeletal muscle sections from
apoE-/- mice. Use of VEGF sense control probe
did not result in an identifiable signal (Figure 6).
|
Absolute T-Cell Count Is Not Reduced in ApoE-/-
Mice
Because histopathological examination disclosed a paucity of
infiltrating T lymphocytes in the ischemic limbs of
apoE-/- mice, flow cytometry was performed on
blood obtained from C57 and apoE-/- mice (n=16)
to determine expression of CD-3, CD-4, and CD-8.
The percentage of circulating CD-3–positive cells was reduced by 26.8% in apoE-/- mice compared with nontransgenic mice of similar (C57) background (26.0±1.8% versus 35.5±4.1%, P=0.06). The mean number of total leukocytes among apoE-/- mice, however, was more than that measured for the C57 mice (7990±850 versus 3930±280, P=0.001). Thus, the total number of T cells in the apoE mice was not reduced but in fact exceeded the number measured in the C57 wild-type mice. With regard to T-cell subtypes, the CD-4/CD-8 ratio was 1.43±0.2 for apoE-/- mice versus 1.40±0.1 in C57 controls.
Angiogenesis Is Retarded in Nude Mice
If T cells constitute a critical source of VEGF, we reasoned that
angiogenesis should be similarly retarded in nude mice. Indeed, in
congenitally athymic C57BL/6J-nu mice (Jackson Laboratory), routine
femoral arterial resection led to early (<10 days) and
extensive limb necrosis (Figure 7). To
permit limb survival beyond 10 days, the femoral artery was excised
slightly more distally; this extended limb survival to 14 days after
surgery. Recovery of blood flow, however, remained severely impaired,
resulting in toe necrosis by day 15, at which time the experiments were
terminated.
|
Necropsy examination 14 days after surgery disclosed a marked reduction
in capillary density in nude compared with C57 mice: CD-31
immunostaining showed extensive territory lacking
capillaries with only rare foci of neovascularization (Figure 8). In the absence of T cells in the
ischemic limbs of nude mice, the macrophage component
of the inflammatory cell infiltrate was increased in comparison to C57
mice (Table, Figure 5). Immunostaining of
sections from these same tissues disclosed a marked decrease in VEGF
expression within 14 days of follow-up compared with control strains
(Figure 8).
|
Intramuscular Adenoviral Murine VEGF Gene Transfer Augments
Angiogenesis in ApoE-/- Mice
If angiogenesis is retarded in apoE-/-
mice as a result of reduced VEGF expression, then VEGF replacement
should augment angiogenesis. Ischemic hindlimb skeletal
myocytes of apoE-/- mice transfected with
adenoviral murine VEGF in fact displayed augmented VEGF expression as
early as day 3 (Figure 9) compared with
apoE-/- mice transfected with
nls-LacZ. Within 21 days, hindlimb blood flow was improved
in apoE-/- mice transfected with VEGF compared
with nls-LacZ. Over 35 days, blood flow recovery in
VEGF-transfected apoE-/- mice was equivalent to
that in C57 mice (Figure 10).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
These findings provide inferential evidence that collateral vessel development is impaired in the setting of hypercholesterolemia. Hypercholesterolemia due to an inherited deficiency of apoE lipoprotein was associated with retarded restoration of blood flow to an ischemic limb. Although capillary density was progressively augmented in C57 control mice, capillary density in the ischemic limb of apoE-/- mice was, by comparison, persistently reduced to a statistically significant degree.
The apparent reduction in collateral vessel development in the apoE-/- mice was associated with a relative reduction in the levels of VEGF protein in the ischemic limb compared with C57 mice. This finding is consistent with previous studies in which targeted disruption of the gene encoding for VEGF leads to impaired angiogenesis.8 9 The apparent restoration of collateral vessel development by constitutive overexpression of VEGF in apoE-/- mice confirms the critical role of VEGF in directing hindlimb collateral vessel development. Moreover, these experiments suggest that even in the face of disordered lipid metabolism, VEGF receptor expression and function are sufficiently preserved to permit collateral vessel augmentation in response to exogenously administered ligand.
Immunostaining of tissue sections harvested from ischemic limbs of the C57 mice clearly demonstrated that skeletal myocytes constitute an important source of endogenous VEGF synthesis. Smooth muscle cells,10 ischemic myocardium,11 and circulating monocytes12 have been shown to express VEGF. In addition, however, cell-specific immunostaining demonstrated large numbers of T cells among inflammatory cell infiltrates in the ischemic limb of the C57 mice; in contrast, few T cells were observed in tissue sections from the ischemic hindlimbs of apoE-/- mice.
The finding that leukocytes may synthesize and export angiogenic cytokines has been reported previously.13 14 15 16 Blotnick et al13 showed that cultured T lymphocytes isolated from normal human peripheral blood could synthesize heparin-binding epidermal-like growth factor (primarily from CD4+ cells) and basic fibroblast growth factor (bFGF, from CD4+ and CD8+ cells). Freeman et al15 subsequently showed that CD4+ and CD8+ cells could export bioactive concentrations of VEGF as well; moreover, tumor-infiltrating lymphocytes in tissue sections cut from bladder cancers were shown to stain positively for VEGF protein. These results were confirmed at the mRNA level by Iijima et al.16
To specifically investigate the relative magnitude of VEGF contributed by T cells to restoration of blood flow in the ischemic limb, we performed the identical surgical procedure used to establish hindlimb ischemia in the C57 and apoE-/- mice on athymic nude mice. None of the latter survived beyond 10 days without experiencing severe limb necrosis. Even when the surgical procedure was modified by excision of a shorter segment of the femoral artery, toe necrosis routinely developed within 15 days. These experiments thus suggest that VEGF contributed by T cells in the setting of tissue ischemia is critical for timely development of collateral vessel growth and restoration of blood flow to the ischemic district.
Although athymic nude mice are by definition T cell–deficient, this was not the case in the apoE-/- mice. The absolute T-cell number in apoE-/- mice was in fact 92.8% higher than in C57 mice. Absent reduced T-cell numbers, the marked reduction in T-cell infiltrates seen in tissue sections from the apoE-/- ischemic limbs implies an associated defect in T-cell function. Although not previously associated with disordered lipid metabolism, T-cell dysfunction acquired with age17 constitutes a potential precedent for the present findings. Stohlawetz et al18 in fact showed that transendothelial migration of human T cells may be compromised in elderly versus young subjects, although the basis for this defect in transmigration was not disclosed. More recently, several groups19 20 21 have shown that T-cell recruitment is in part determined by preserved affinity for specific cell adhesion molecules. It is important to underscore the fact that VEGF expression in T cells is upregulated by hypoxia15 ; thus, failure of T cells to exit the circulation and infiltrate the ischemic tissue precludes what may be an important compensatory mechanism for achieving site-specific increase in VEGF synthesis.
The principle that disordered lipid metabolism may impair angiogenesis is further supported by other recent experimental findings. Murugesan and Fox22 established that oxidized LDL inhibits EC motility. Chen et al23 24 showed that bFGF reverses atherosclerotic impairment of capillary-like microtubes, which develop in vitro from explants of human coronary arteries. Thus, these preliminary reports, together with the present findings, provide compelling evidence that lipid disorders may retard angiogenesis but do not preclude a favorable response to cytokine therapy.
|
Acknowledgments |
|---|
This study was supported in part by NIH grants HL-02824, HL-53354, and HL-57516 to Dr Isner and grants from the University Hospital of Bordeaux and the French Ministry of Foreign Affairs (La Voisier grant) to Dr Couffinhal.
Received December 31, 1998; revision received February 19, 1999; accepted March 16, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Plump A, Smith JD, Hayek T, Aalto-Setala K, Walsh A, Verstuyft JG, Rubin EM, Breslow JL. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992;71:343–353.[Medline] [Order article via Infotrieve]
2.
Zhang SH, Reddick RL, Piedrahita JA, Maeda N.
Spontaneous hypercholesterolemia and
arterial lesions in mice lacking apolipoprotein E.
Science. 1992;258:468–471.
3. Couffinhal T, Silver M, Zheng LP, Kearney M, Witzenbichler B, Isner JM. A mouse model of angiogenesis. Am J Pathol. 1998;152:1667–1679.[Abstract]
4. Murohara T, Asahara T, Silver M, Bauters C, Masuda H, Kalka C, Kearney M, Chen D, Symes JF, Fishman MC, Huang PL, Isner JM. Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. J Clin Invest. 1998;101:2567–2578.[Medline] [Order article via Infotrieve]
5. Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis: correlation in invasive breast carcinoma. N Engl J Med. 1991;324:1–8.[Abstract]
6. Vecci A, Garlanda C, Lampugnani MG, Resnati C, Matteucci C, Stoppacciaro A, Schnurch H, Risau W, Ruco L, Mantovani A, Dejana E. Monoclonal antibodies specific for endothelial cells of mouse blood vessels: their application in the identification of adult and embryonic endothelium. Eur J Cell Biol. 1994;63:247–254.[Medline] [Order article via Infotrieve]
7. Vanzulli S, Gazzaniga S, Braidot MF, Vecci A, Montovani A, Wainstok de Calmanovici R. Detection of endothelial cells by MEC 13.3 monoclonal antibody in mice mammary tumors. Biocell. 1997;21:39–46.[Medline] [Order article via Infotrieve]
8. Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, Declercq C, Pawling J, Moons L, Collen D, Risau W, Nagy A. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996;380:435–439.[Medline] [Order article via Infotrieve]
9. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O'Shea KS, Powell-Braxton L, Hilan KJ, Moore MW. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996;380:439–442.[Medline] [Order article via Infotrieve]
10. Tsurumi Y, Murohara T, Krasinski K, Dongfen C, Witzenbichler B, Kearney M, Couffinhal T, Isner JM. Reciprocal relationship between VEGF and NO in the regulation of endothelial integrity. Nature Med. 1997;3:879–886.[Medline] [Order article via Infotrieve]
11. Li J, Hampton T, Morgan JP, Simons M. Stretch-induced VEGF expression in the heart. J Clin Invest. 1997;100:18–24.[Medline] [Order article via Infotrieve]
12. Arras M, Ito WD, Scholz D, Winkler B, Schaper J, Schaper W. Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J Clin Invest. 1998;101:40–50.[Medline] [Order article via Infotrieve]
13.
Blotnick S, Peoples GE, Freeman R, Eberlein TJ,
Klagsbrun M. T lymphocytes synthesize and export heparin-binding
epidermal growth factor-like growth factor and basic fibroblast growth
factor, mitogens for vascular cells and fibroblasts: differential
production and release by CD4+ and
CD8+ T cells. Proc Natl Acad Sci
U S A. 1994;91:2890–2894.
14. Fromer CH, Klintworth GK. An evaluation of the role of leukocytes in the pathogenesis of experimentally induced corneal vascularization. Am J Pathol. 1976;82:157–170.
15.
Freeman MR, Schneck FX, Gagnon ML, Corless C, Soker S,
Niknejad K, Peoples GE, Klagsbrun M. Peripheral blood T
lymphocytes and lymphocytes infiltrating human cancers express vascular
endothelial growth factor: a potential role for T cells
in angiogenesis. Cancer Res. 1995;55:4140–4145.
16. Iijima K, Yoshikawa N, Nakamura H. Activation-induced expression of vascular permeability factor by human peripheral T cells: a non-radioisotopic semiquantitative reverse transcription-polymerase chain reaction assay. J Immunol Methods. 1996;196:199–209.[Medline] [Order article via Infotrieve]
17. Miller RA. The aging immune system: primer and prospectus. Science. 1996;273:70–74.[Abstract]
18. Stohlawetz P, Kolussi T, Jahandideh-Kazempour S, Kudlacek S, Graninger W, Willvonseder R, Pietschmann P. The effect of age on the transendothelial migration of human T lymphocytes. Scand J Immunol. 1996;44:530–534.[Medline] [Order article via Infotrieve]
19.
Gerszten RE, Luscinskas FW, Ding HT, Dichek DA,
Stoolman LM, Gimbrone MA, Rosenzweig A. Adhesion of memory lymphocytes
to vascular cell adhesion molecule-1–transduced human vascular
endothelial cells under simulated
physiological flow conditions in vitro. Circ
Res. 1996;79:1205–1215.
20.
Stemme S, Holm J, Hansson GK. T lymphocytes in human
atherosclerotic plaques are memory cells expressing CD45RO and the
integrin VLA-1. Arterioscler Thromb. 1992;12:206–211.
21. Austrup F, Vestweber D, Borges E, Lohning M, Brauer R, Herz U, Renz H, Hallmann R, Scheffold A, Radbruch A, Hamann A. P- and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflamed tissues. Nature. 1997;385:81–83.[Medline] [Order article via Infotrieve]
22. Murugesan G, Fox PL. Role of lysophosphatidylcholine in the inhibition of endothelial cell motility by oxidized low density lipoprotein. J Clin Invest. 1996;97:2736–2744.[Medline] [Order article via Infotrieve]
23. Chen CH, Nguyen HH, Weilbaecher D, Luo S, Gotto AM Jr, Henry PD. Basic fibroblast growth factor reverses atherosclerotic impairment of human coronary angiogenesis-like response in vitro. Atherosclerosis. 1995;116:261–268.[Medline] [Order article via Infotrieve]
24.
Chen C-H, Cartwright J Jr, Li Z, Lou S, Nguyen HH,
Gotto AM Jr, Henry PD. Inhibitory effects of
hypercholesterolemia and ox-LDL on
angiogenesis-like endothelial growth in rabbit aortic
explants: essential role of basic fibroblast growth factor.
Arterioscler Thromb Vasc Biol. 1997;17:1303–1312.
This article has been cited by other articles:
 |
|
 |
|
  S. Dussault, F. Maingrette, C. Menard, S.-E. Michaud, P. Haddad, J. Groleau, J. Turgeon, G. Perez, and A. Rivard Sildenafil Increases Endothelial Progenitor Cell Function and Improves Ischemia-Induced Neovascularization in Hypercholesterolemic Apolipoprotein E-Deficient Mice Hypertension, November 1, 2009; 54(5): 1043 - 1049. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zouggari, H. Ait-Oufella, L. Waeckel, J. Vilar, C. Loinard, C. Cochain, A. Recalde, M. Duriez, B. I. Levy, E. Lutgens, et al. Regulatory T Cells Modulate Postischemic Neovascularization Circulation, October 6, 2009; 120(14): 1415 - 1425. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Haddad, S. Dussault, J. Groleau, J. Turgeon, S.-E. Michaud, C. Menard, G. Perez, F. Maingrette, and A. Rivard Nox2-Containing NADPH Oxidase Deficiency Confers Protection From Hindlimb Ischemia in Conditions of Increased Oxidative Stress Arterioscler Thromb Vasc Biol, October 1, 2009; 29(10): 1522 - 1528. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Silvestre and B. I. Levy Circulating progenitor cells and cardiovascular outcomes: latest evidence on angiotensin-converting enzyme inhibitors Eur. Heart J. Suppl., August 1, 2009; 11(suppl_E): E17 - E21. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Tsunoda, H. Sakurai, Y. Saito, Y. Ueno, K. Koizumi, and I. Saiki Massive T-Lymphocyte Infiltration into the Host Stroma Is Essential for Fibroblast Growth Factor-2-Promoted Growth and Metastasis of Mammary Tumors via Neovascular Stability Am. J. Pathol., February 1, 2009; 174(2): 671 - 683. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. van Oostrom, O. van Oostrom, P. H. A. Quax, M. C. Verhaar, and I. E. Hoefer Insights into mechanisms behind arteriogenesis: what does the future hold? J. Leukoc. Biol., December 1, 2008; 84(6): 1379 - 1391. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Ouchi, Y. Oshima, K. Ohashi, A. Higuchi, C. Ikegami, Y. Izumiya, and K. Walsh Follistatin-like 1, a Secreted Muscle Protein, Promotes Endothelial Cell Function and Revascularization in Ischemic Tissue through a Nitric-oxide Synthase-dependent Mechanism J. Biol. Chem., November 21, 2008; 283(47): 32802 - 32811. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. You, C. Cochain, C. Loinard, J. Vilar, B. Mees, M. Duriez, B. I. Levy, and J.-S. Silvestre Combination of the Angiotensin-Converting Enzyme Inhibitor Perindopril and the Diuretic Indapamide Activate Postnatal Vasculogenesis in Spontaneously Hypertensive Rats J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 766 - 773. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kinnaird, E. Stabile, S. Zbinden, M.-S. Burnett, and S. E. Epstein Cardiovascular risk factors impair native collateral development and may impair efficacy of therapeutic interventions Cardiovasc Res, May 1, 2008; 78(2): 257 - 264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-S. Silvestre, Z. Mallat, A. Tedgui, and B. I. Levy Post-ischaemic neovascularization and inflammation Cardiovasc Res, May 1, 2008; 78(2): 242 - 249. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. T. van Beem, W. A. Noort, C. Voermans, M. Kleijer, A. ten Brinke, S. M. van Ham, C. E. van der Schoot, and J. J. Zwaginga The Presence of Activated CD4+ T Cells Is Essential for the Formation of Colony-Forming Unit-Endothelial Cells by CD14+ Cells J. Immunol., April 1, 2008; 180(7): 5141 - 5148. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Lefevre, S.-E. Michaud, P. Haddad, S. Dussault, C. Menard, J. Groleau, J. Turgeon, and A. Rivard Moderate consumption of red wine (cabernet sauvignon) improves ischemia-induced neovascularization in ApoE-deficient mice: effect on endothelial progenitor cells and nitric oxide FASEB J, December 1, 2007; 21(14): 3845 - 3852. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. van Weel, R.E.M. Toes, L. Seghers, M.M.L. Deckers, M.R. de Vries, P.H. Eilers, J. Sipkens, A. Schepers, D. Eefting, V.W.M. van Hinsbergh, et al. Natural Killer Cells and CD4+ T-Cells Modulate Collateral Artery Development Arterioscler Thromb Vasc Biol, November 1, 2007; 27(11): 2310 - 2318. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Ochoa, D. Sun, S. M. Reyes-Reyna, L. L. Waite, J. E. Michalek, L. M. McManus, and P. K. Shireman Delayed angiogenesis and VEGF production in CCR2 / mice during impaired skeletal muscle regeneration Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2007; 293(2): R651 - R661. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Penuelas, X. L. Aranguren, G. Abizanda, J. M. Marti-Climent, M. Uriz, M. Ecay, M. Collantes, G. Quincoces, J. A. Richter, and F. Prosper 13N-Ammonia PET as a Measurement of Hindlimb Perfusion in a Mouse Model of Peripheral Artery Occlusive Disease J. Nucl. Med., July 1, 2007; 48(7): 1216 - 1223. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Capoccia, R. M. Shepherd, and D. C. Link G-CSF and AMD3100 mobilize monocytes into the blood that stimulate angiogenesis in vivo through a paracrine mechanism Blood, October 1, 2006; 108(7): 2438 - 2445. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E. Bergmann, I. E. Hoefer, B. Meder, H. Roth, N. van Royen, S. M. Breit, M. M. Jost, S. Aharinejad, S. Hartmann, and I. R. Buschmann Arteriogenesis depends on circulating monocytes and macrophage accumulation and is severely depressed in op/op mice J. Leukoc. Biol., July 1, 2006; 80(1): 59 - 65. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. van Weel, M. de Vries, P. J. Voshol, R. E. Verloop, P. H.C. Eilers, V. W.M. van Hinsbergh, J. H. van Bockel, and P. H.A. Quax Hypercholesterolemia Reduces Collateral Artery Growth More Dominantly Than Hyperglycemia or Insulin Resistance in Mice Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): 1383 - 1390. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Li, W. Shen, R. Gill, A. Corbly, B. Jones, R. Belagaje, Y. Zhang, S. Tang, Y. Chen, Y. Zhai, et al. High-Resolution Quantitative Computed Tomography Demonstrating Selective Enhancement of Medium-Size Collaterals by Placental Growth Factor-1 in the Mouse Ischemic Hindlimb Circulation, May 23, 2006; 113(20): 2445 - 2453. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Stabile, T. Kinnaird, A. la Sala, S. K. Hanson, C. Watkins, U. Campia, M. Shou, S. Zbinden, S. Fuchs, H. Kornfeld, et al. CD8+ T Lymphocytes Regulate the Arteriogenic Response to Ischemia by Infiltrating the Site of Collateral Vessel Development and Recruiting CD4+ Mononuclear Cells Through the Expression of Interleukin-16 Circulation, January 3, 2006; 113(1): 118 - 124. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Tirziu, K. L. Moodie, Z. W. Zhuang, K. Singer, A. Helisch, J. F. Dunn, W. Li, J. Singh, and M. Simons Delayed Arteriogenesis in Hypercholesterolemic Mice Circulation, October 18, 2005; 112(16): 2501 - 2509. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kitagawa, Y. Yagita, T. Sasaki, S. Sugiura, E. Omura-Matsuoka, T. Mabuchi, K. Matsushita, and M. Hori Chronic Mild Reduction of Cerebral Perfusion Pressure Induces Ischemic Tolerance in Focal Cerebral Ischemia Stroke, October 1, 2005; 36(10): 2270 - 2274. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Izumi, S. Kim-Mitsuyama, M. Yoshiyama, T. Omura, M. Shiota, A. Matsuzawa, T. Yukimura, T. Murohara, M. Takeya, H. Ichijo, et al. Important Role of Apoptosis Signal-Regulating Kinase 1 in Ischemia-Induced Angiogenesis Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1877 - 1883. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Chalothorn, H. Zhang, J. A. Clayton, S. A. Thomas, and J. E. Faber Catecholamines augment collateral vessel growth and angiogenesis in hindlimb ischemia Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H947 - H959. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
L. Waeckel, Z. Mallat, S. Potteaux, C. Combadiere, M. Clergue, M. Duriez, L. Bao, C. Gerard, B. J. Rollins, A. Tedgui, et al. Impairment in Postischemic Neovascularization in Mice Lacking the CXC Chemokine Receptor 3 Circ. Res., March 18, 2005; 96(5): 576 - 582. [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]
|
|
|
|
|
|
B. H. Annex and M. Simons Growth factor-induced therapeutic angiogenesis in the heart: protein therapy Cardiovasc Res, February 15, 2005; 65(3): 649 - 655. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Murasawa and T. Asahara Endothelial Progenitor Cells for Vasculogenesis Physiology, February 1, 2005; 20(1): 36 - 42. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V Achan, H. Ho, C Heeschen, M Stuehlinger, J. Jang, M Kimoto, P Vallance, and J. Cooke ADMA regulates angiogenesis: genetic and metabolic evidence Vascular Medicine, February 1, 2005; 10(1): 7 - 14. [Abstract] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
D. Scholz and W. Schaper Preconditioning of arteriogenesis Cardiovasc Res, February 1, 2005; 65(2): 513 - 523. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G. Lloyd, B. M. Prior, H. Li, H. T. Yang, and R. L. Terjung VEGF receptor antagonism blocks arteriogenesis, but only partially inhibits angiogenesis, in skeletal muscle of exercise-trained rats Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H759 - H768. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Wolf, C. A. Hubel, C. Lam, M. Sampson, J. L. Ecker, R. B. Ness, A. Rajakumar, A. Daftary, A. S. M. Shakir, E. W. Seely, et al. Preeclampsia and Future Cardiovascular Disease: Potential Role of Altered Angiogenesis and Insulin Resistance J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6239 - 6243. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 H. Niiyama, H. Kai, T. Yamamoto, T. Shimada, K.-I. Sasaki, T. Murohara, K. Egashira, and T. Imaizumi Roles of endogenous monocyte chemoattractant protein-1 in ischemia-induced neovascularization J. Am. Coll. Cardiol., August 4, 2004; 44(3): 661 - 666. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
S. E. Epstein, E. Stabile, T. Kinnaird, C. W. Lee, L. Clavijo, and M. S. Burnett Janus Phenomenon: The Interrelated Tradeoffs Inherent in Therapies Designed to Enhance Collateral Formation and Those Designed to Inhibit Atherogenesis Circulation, June 15, 2004; 109(23): 2826 - 2831. [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
A. Germani, A. Di Carlo, A. Mangoni, S. Straino, C. Giacinti, P. Turrini, P. Biglioli, and M. C. Capogrossi Vascular Endothelial Growth Factor Modulates Skeletal Myoblast Function Am. J. Pathol., October 1, 2003; 163(4): 1417 - 1428. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Stabile, M. S. Burnett, C. Watkins, T. Kinnaird, A. Bachis, A. la Sala, J. M. Miller, M. Shou, S. E. Epstein, and S. Fuchs Impaired Arteriogenic Response to Acute Hindlimb Ischemia in CD4-Knockout Mice Circulation, July 15, 2003; 108(2): 205 - 210. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
N. van Royen, I. Hoefer, M. Bottinger, J. Hua, S. Grundmann, M. Voskuil, C. Bode, W. Schaper, I. Buschmann, and J.J. Piek Local Monocyte Chemoattractant Protein-1 Therapy Increases Collateral Artery Formation in Apolipoprotein E-Deficient Mice but Induces Systemic Monocytic CD11b Expression, Neointimal Formation, and Plaque Progression Circ. Res., February 7, 2003; 92(2): 218 - 225. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N van Royen, I Hoefer, I Buschmann, S Kostin, M Voskuil, C. Bode, W Schaper, and J.J Piek Effects of local MCP-1 protein therapy on the development of the collateral circulation and atherosclerosis in Watanabe hyperlipidemic rabbits Cardiovasc Res, January 1, 2003; 57(1): 178 - 185. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
I. E. Hoefer, N. van Royen, J. E. Rectenwald, E. J. Bray, Z. Abouhamze, L. L. Moldawer, M. Voskuil, J. J. Piek, I. R. Buschmann, and C. K. Ozaki Direct Evidence for Tumor Necrosis Factor-{alpha} Signaling in Arteriogenesis Circulation, April 9, 2002; 105(14): 1639 - 1641. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
J. Rockstroh and B. G. Brown Coronary Collateral Size, Flow Capacity, and Growth: Estimates From the Angiogram in Patients With Obstructive Coronary Disease Circulation, January 15, 2002; 105(2): 168 - 173. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
C. Emanueli, M. B. Salis, T. Stacca, L. Gaspa, J. Chao, L. Chao, A. Piana, and P. Madeddu Rescue of Impaired Angiogenesis in Spontaneously Hypertensive Rats by Intramuscular Human Tissue Kallikrein Gene Transfer Hypertension, July 1, 2001; 38(1): 136 - 141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. van Royen, J. J. Piek, I. Buschmann, I. Hoefer, M. Voskuil, and W. Schaper Stimulation of arteriogenesis; a new concept for the treatment of arterial occlusive disease Cardiovasc Res, February 16, 2001; 49(3): 543 - 553. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
H. Iwaguro, J.-i. Yamaguchi, C. Kalka, S. Murasawa, H. Masuda, S.-i. Hayashi, M. Silver, T. Li, J. M. Isner, and T. Asahara Endothelial Progenitor Cell Vascular Endothelial Growth Factor Gene Transfer for Vascular Regeneration Circulation, February 12, 2002; 105(6): 732 - 738. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||