© 1997 American Heart Association, Inc.
Articles |
Tie2 Expression and Phosphorylation in Angiogenic and Quiescent Adult Tissues
From the Department of Cell Biology (A.L.W.), the Department of Pathology (Z.A.H., M.W.D., C.S.G.), the Department of Radiation Oncology (M.W.D.), the Department of Medicine, Divisions of Hematology & Medical Oncology (C.S.G.) and the Division of Cardiology (K.G.P.), and the Department of Pharmacology (K.G.P.), Duke University Medical Center, Durham, NC, and the Max-Planck-Institut fur Biochemie (S.W.), Planegg-Marlinsried, Germany.
Correspondence to Dr Kevin G. Peters, Box 3623, Duke University Medical Center, 430 Sands Bldg, Research Drive, Durham, NC 27710. E-mail kgp{at}hodgkin.mc.duke.edu
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Abstract |
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Abstract Angiogenesis, the process of new vessels sprouting from the existing vasculature, is a critical process during early development. However, angiogenesis rarely occurs in the adult, except in response to cyclic hormonal stimulation in the ovary and uterus, in response to injury, and in response to pathological conditions such as tumorigenesis and diabetes mellitus. Tie2 (also known as Tek) is a novel endothelium-specific receptor tyrosine kinase, which has been demonstrated to be essential for the development of the embryonic vasculature; Tie2 knockout mice die by embryonic day 10.5 with specific defects in the formation of microvessels. Tie2 is downregulated later in embryogenesis, and its function in the adult has been relatively unexplored. To gain insight into the potential functions of Tie2 in the adult vasculature, Tie2 expression was examined in adult tissues undergoing angiogenesis and in quiescent tissues. Tie2 expression was localized by immunohistochemistry to the endothelium of neovessels in rat tissues undergoing angiogenesis during hormonally stimulated follicular maturation and uterine development and in healing skin wounds. Immunoprecipitation and RNase protection assay demonstrated upregulation of Tie2 protein and mRNA in rat and mouse skin wounds, respectively. Moreover, Tie2 immunoprecipitated from skin wounds was tyrosine-phosphorylated, indicating active downstream signaling. Surprisingly, Tie2 was also expressed in the entire spectrum of the quiescent vasculature (arteries, veins, and capillaries) in a wide range of adult tissues, and Tie2 immunoprecipitated from quiescent adult tissues was also tyrosine-phosphorylated. Together, these results suggest a dual function for Tie2 in adult tissues involving both angiogenesis and vascular maintenance.
Key Words: receptor tyrosine kinase • endothelium • angiogenesis • wound healing • Tie2
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Introduction |
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Angiogenesis, the sprouting of new vessels from the existing vasculature, is a tightly controlled process that plays its most obvious role in early development. Although the potential for angiogenesis is maintained throughout the lifetime of an organism, once the vasculature has been established, the endothelium remains extraordinarily quiescent in the adult.1 2 The hormonal control of the ovary and uterus in reproduction provides perhaps the only normal physiological exception to this rule.3 All other activation of angiogenesis during adulthood occurs in response to injury or pathological processes such as tumorigenesis and diabetic retinopathy.4 5 6
Although the mechanisms that drive angiogenesis have not been fully elucidated, a large body of evidence has established important roles for endothelial RTKs such as VEGF and FGF receptors and their cognate growth factors.7 Recently, a novel family of endothelium-specific RTKs, the Tie family, has been identified, consisting of the receptors Tie1 and Tie2 (also known as Tek).8 9 10 11 12 13 14 Not only were Tie1 and Tie2 expressed predominantly in vascular endothelial cells during embryogenesis,14 15 but functional disruption of either Tie1 or Tie2 in transgenic mice was lethal secondary to distinct defects in vascular development.16 17 18 Disruption of Tie1 function led to perinatal lethality, with defects suggesting a role in vascular integrity. However, disruption of Tie2 function led to early embryonic lethality, with defects in the microvasculature suggesting a role in embryonic angiogenesis. Although these studies have established a role for Tie1 and Tie2 during embryonic vascular formation, little is presently known regarding the function of these receptors in the mature vasculature.
In order to gain insight into the function of Tie2 in the mature vasculature, the present study explores the regulation of Tie2 expression in adult tissues. Using a monoclonal antibody developed in our laboratory, we have demonstrated that Tie2 is expressed in the endothelium during angiogenesis in the hormone-stimulated ovary and uterus and in healing skin wounds. Unexpectedly, Tie2 was also broadly expressed in the endothelium of the quiescent adult vasculature. Moreover, Tie2 was tyrosine-phosphorylated in both angiogenic tissues and quiescent adult tissues. Taken together, these results suggest that in adult tissues, Tie2 signaling may have a dual function in both vascular growth and vascular maintenance.
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Materials and Methods |
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Animal Protocols
Superovulation
Thirty-day-old Wistar rats (Charles River Laboratories, Raleigh, NC) were given an intraperitoneal injection of 50 IU of PMSG (Sigma Chemical Co) in 0.75 mL of 0.9% NaCl between 9:00 and 10:00 AM of day 1, followed by 25 IU of hCG (Sigma) in 0.4 mL of 0.9% NaCl between 9:00 and 10:00 AM of day 3. Animals were killed between 4:00 and 5:00 PM of days 1 to 4 by isoflurane anesthesia, followed by cervical dislocation.
Wounding
Three-month-old Fischer rats (Charles River Laboratories,
Raleigh, NC) were anesthetized with an intramuscular injection
of ketamine (70 mg/kg) and an
intraperitoneal injection of pentobarbital (40
mg/kg), then shaved, and depilated (Nair). Sixteen 5-mm biopsy
punch wounds were made on the dorsal skin. The punches from day 0
served as an unwounded skin control; wounds were harvested on days 1,
3, 5, 7, and 9 after wounding for Western blotting and on days 2, 4, 5,
6, and 8 for immunohistochemical analysis. One rat was killed
for each time point, and the experiments were performed in
duplicate.
Organ Blots
Three-month-old Wistar rats were killed, and their organs were
removed. Rats were killed by an intravenous overdose of
pentobarbital.
Tissue Preparation
Dissected organs were fixed in 4%
paraformaldehyde/PBS for 1 to 3 hours, then
equilibrated in 30% sucrose overnight, and embedded in Tissue Tek OCT
(Miles). Skin wounds were snap-frozen in OCT.
Immunohistochemistry
MoAb33 was raised against the extracellular domain of human Tie2
protein. Although MoAb33 exhibits cross-reactivity with mouse Tek in
enzyme-linked immunosorbent assays, it does not recognize the closely
related Tie1 protein in Western blots (P. Rao, K. Peters, unpublished
data, 1996). Tie2 protein was localized with MoAb33 at 1:1000 in PBS,
MRC-OX-43 (Serotec) was used at 1:400 as a marker for rat
endothelium, and IgGK (Sigma) at 1:1000 was used as a
negative control. Slides were dried overnight at room temperature.
Snap-frozen sections were postfixed in 4%
paraformaldehyde for 20 minutes, treated in 3%
hydrogen peroxide/PBS for 15 minutes, blocked in 5% normal rabbit
serum for 20 minutes, blocked with biotin/avidin for 15 minutes each
(Vector), and incubated with the following: primary antibody for 2
hours at room temperature, biotinylated rabbit-anti mouse IgG (Dako) at
1:400 for 30 minutes, and Vector Elite ABC biotin-avidin-peroxidase
complex for 30 minutes; sections were then developed with
diaminobenzidine and diaminobenzidine enhancer (Vector), counterstained
with hematoxylin, and mounted.
RNase Protection Assay
Six full-thickness excisional wounds were made on the backs of
BALB/c mice by excising skin and panniculus carnosus. The wounds were
allowed to dry to form a scab. The complete wound including the scab
and 2 mm of the epithelial margins was excised at each time point
(1, 3, 5, 7, and 13 days after wounding). A similar amount of skin from
the backs of three nonwounded animals was used as a control. In every
experiment, the wounds from four animals (24 wounds) were combined,
immediately frozen in liquid nitrogen, and stored at -70°C until
used for RNA isolation. Antisense Tie2 probe was generated by
linearizing a murine Tie2 extracellular domain cDNA in pcrScript
(Stratagene) with Bbs I and transcribing with T7 RNA
polymerase (Promega) in the presence of [32P]UTP
(Amersham) to yield a 271-bp probe of bases 2168 to 2439 (Genbank
Accession No. X67553). Each RNA (1 µg) was loaded on a 1% agarose
gel before hybridization as an internal standard. Samples (50 µg) of
total RNA were hybridized with 1x105 cpm of
32P-labeled antisense RNA probe overnight at 42°C and
then digested with RNase A and T1 for 40 minutes at 30°C. The digests
were resolved on 5% polyacrylamide gels and visualized by
autoradiography.
Western Blotting
Tissue samples were homogenized in modified RIPA
buffer (50 mmol/L Tris [pH 7.4], 1% IGEPAL CA-630
(Sigma), 0.25% sodium deoxycholate, 150 mmol/L NaCl,
1 mmol/L EDTA, 1 mmol/L phenylmethylsulfonyl
fluoride, and 1 µg/mL aprotinin, leupeptin, and
pepstatin). EC-RF24 cells (a gift from Dr H. Pannekoek, University
of Amsterdam, the Netherlands)19 were cultured on 2%
gelatin (Sigma)/PBS in endothelial cell growth medium with 2% FBS
(Clonetics) and serum-starved in endothelial cell basal medium
(Clonetics). Cells were lysed in modified RIPA buffer for 15 minutes at
4°C with rocking and then scraped from the plates. Protein samples (1
mg) were immunoprecipated via incubation with 1 µg MoAb33 for 2 hours
at 4°C and with protein G–agarose beads (Santa Cruz Biotechnology)
for an additional 1 hour. The beads were then washed three times in
lysis buffer, once in 50 mmol/L Tris/1 mmol/L
vanadate, resuspended in Laemmli loading buffer, and separated on 8%
SDS-polyacrylamide gels. Nitrocellulose membranes (Schleicher &
Schuell, Inc) were blocked with 5% milk/TBST for 1 hour, probed with
MoAb33 (at 1:10 000 with TBST) or 4G10 (UBI) and 
-mouse
IgG–horseradish peroxidase (Promega), and developed using enhanced
chemiluminescence (Amersham). Stripping of blots was performed
overnight at room temperature in TBST (pH 2.4). A vanadate-pretreated
lysate of 3T3 cells stably transfected with the full-length Tie2 cDNA
served as the control. Laser densitometry was performed with an LKB
UltroScan XL.
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Results |
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Tie2 Is Expressed and Tyrosine-Phosphorylated in the Vascular Endothelium of Angiogenic Tissues
In order to investigate the expression of Tie2 in the context of hormonally induced angiogenesis in the ovary, reproductively immature female rats were treated with PMSG on day 1 to induce follicular maturation and with hCG on day 3 to induce ovulation. Localization of Tie2 expression was examined by immunohistochemistry on days 1 to 4 of treatment. In the early stages of follicular development, Tie2 expression was confined to the stroma surrounding the developing follicles (Fig 1A
). As
follicular maturation proceeded, Tie2 expression was detected in the
newly vascularized theca interna (Fig 1B). No staining was observed in
the avascular granulosa cells of the mature follicle. After ovulation,
Tie2 expression was detected in the endothelium of
microvessels invading the previously avascular granulosa of the
developing corpus luteum (Fig 1C).
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In addition to characteristic changes in the ovary, PMSG treatment also
results in the proliferation and neovascularization of the endometrium.
Gonadotropin-induced ovarian steroid production
stimulated endometrial development in preparation for implantation. As
in developing ovarian vessels, Tie2 was expressed in the
endothelium of the developing endometrial vasculature
in the hormone-stimulated uterus (Fig 1D
through 1F).
Wound healing is another well-established setting in which to
study angiogenesis in adult animals.20 In order to examine
Tie2 expression during wound-healing angiogenesis, 5-mm punch biopsy
wounds were made on rat dorsal skin and harvested by excision at
various time points after wounding for analysis by
immunohistochemistry (days 2, 4, 5, 6, and 8) and immunoprecipitation
(days 0, 1, 3, 5, 7, and 9). Immunohistochemical staining demonstrated
that Tie2 was expressed on day 2 in the dilated ectatic vessels
surrounding the wound (Fig 2A). By day 4,
the newly formed microvessels invading the wound granulation tissue
strongly expressed Tie2 (Fig 2B). The pattern of Tie2 staining was
identical to that of a rat endothelial marker
(MRC-OX-43, Fig 2E), and no staining was observed with an irrelevant
isotype-matched antibody (IgGK, Fig 2D). By day 8, when wound edges had
contracted and the microvessels had largely regressed, Tie2 expression
was limited to blood vessels at the wound edge (Fig 2C and 2F).
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Western blotting analysis revealed an increase in Tie2
expression after wounding that peaked at day 3, coincident with the
vascularization of the granulation tissue (Fig 3A). Between days 5 and 9 after wounding,
expression returned to near basal levels, coincident with contraction
of the granulation tissue and regression of the neovasculature. This
result was reproduced in duplicate in two independent experiments.
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To substantiate our findings of Tie2 upregulation during wound
angiogenesis, 5-mm excision wounds were made on the dorsal skin of
mice, and wounds were harvested at various time points for RNA
isolation and analysis by RNase protection assay. Closely
paralleling the pattern of Tie2 protein expression in rat skin wounds,
Tie2 mRNA was rapidly upregulated by day 3 after wounding and then
rapidly downregulated by day 13, reflecting vascular growth and
regression in murine skin wounds (Fig 4).21 This result was
reproduced in three independent protection assays using RNAs from
different wound-healing experiments.
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To explore the regulation of Tie2 signaling in wound
angiogenesis, Tie2 immunoprecipitated from rat wound tissue was probed
with an anti-phosphotyrosine antibody. Interestingly, Tie2 tyrosine
phosphorylation could be detected even in control skin.
Tie2 phosphorylation increased after wounding, peaking
at day 3, and subsequently declined to near baseline levels by day 9
(Fig 3B).
Tie2 Is Widely Expressed and
Tyrosine-Phosphorylated in the Vascular
Endothelium of Quiescent Adult Tissues
Since Tie2 was expressed and
tyrosine-phosphorylated in the quiescent vasculature of
the unwounded skin, the expression and phosphorylation
of Tie2 was examined in other angiogenically quiescent adult rat
tissues. By immunohistochemistry, Tie2 expression was localized in the
endothelium of all adult tissues examined (Figs 5 and 6 and
the Table). Tie2 was
homogeneously expressed throughout the vasculature in the
endothelium of arteries, veins, and capillaries. For
example, arteries and veins in the ovary, kidney, and skeletal muscle
strongly expressed Tie2 (Fig 5). In the kidney, Tie2 expression was
detected in both efferent and afferent arterioles and in fenestrated
glomerular capillaries (Fig 6A). Comparison with a negative
control (Fig 6B) and a marker for rat endothelium (Fig 6C) demonstrates staining specificity for vascular
endothelium. Similarly, microvascular
endothelial cells in the brain, heart, and spleen
demonstrated prominent expression of Tie2 (Fig 6D through 6F).
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Immunoprecipitation experiments confirmed that Tie2 was broadly
expressed in the quiescent adult vasculature. Tie2 protein was most
abundant in the lung but was easily detected in all tissues examined,
including liver, kidney, heart, spleen, skin, brain, and skeletal
muscle (Fig 7A and data not shown).
Probing of immunoprecipitated Tie2 with an anti-phosphotyrosine
antibody demonstrated tyrosine phosphorylation of Tie2
in all tissues examined, consistent with active downstream
signaling in quiescent vasculature (Fig 7B).
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To exclude the possibility that Tie2 tyrosine
phosphorylation was an artifact of immunoprecipitation
with MoAb33, Tie2 was immunoprecipitated from lung lysates in parallel
with endothelial cell lysates. ECRF cells, an
HPV16-immortalized human umbilical vascular endothelial
cell line, were either serum-starved overnight or allowed to grow in
normal medium and pretreated with vanadate before lysis. In this
experiment, similar amounts of Tie2 were immunoprecipitated from the
ECRF cells and lung lysates (Fig 8).
However, Tie2 immunoprecipitated from the ECRF cell lysates contained
little detectable phosphotyrosine (even when pretreated with vanadate),
whereas Tie2 from lung lysates contained easily detectable
phosphotyrosine. Therefore, the tyrosine
phosphorylation of immunoprecipitated Tie2 receptor
from tissue extracts is likely to truly reflect Tie2
phosphorylation in vivo.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although a role for Tie2 in embryonic vascular development has been well established, its role in the adult vasculature has been relatively unexplored. Using immunohistochemistry with a Tie2-specific monoclonal antibody, we have shown that Tie2 was expressed in the endothelium of the developing vasculature in two adult tissues: in the hormone-stimulated female reproductive system and in healing skin wounds. Immunoprecipitation and RNase protection assay confirmed Tie2 expression in healing skin wounds, demonstrating rapid upregulation of Tie2 protein and mRNA during the early stages of wound healing, coinciding with wound angiogenesis, and rapid downregulation of Tie2 during the later stages, coinciding with regression of vessels. Moreover, immunoprecipitated Tie2 was tyrosine-phosphorylated, indicating activation of downstream signaling during wound angiogenesis. Unexpectedly, Tie2 was also expressed and phosphorylated throughout the quiescent vasculature of all adult tissues tested. The presence of tyrosine-phosphorylated Tie2 in tissues undergoing angiogenesis and in the quiescent vasculature suggests a dual role for this endothelium-specific receptor in both angiogenesis and in vascular maintenance.
Role of Tie2 During Angiogenesis
Functional Tie2 signaling is required for the proper development
of the embryonic vasculature. Disruption of murine Tie2 function in
transgenic mice resulted in early embryonic lethality secondary to
distinct defects in microvascular development, characterized by reduced
endothelial cell number, abnormal vascular branching,
and compromised endothelial integrity. These findings
demonstrated that Tie2 function was not required for the earliest
stages of endothelial differentiation and vascular
patterning but was crucial for the formation of the microvasculature
during embryonic angiogenesis. The results of the present study are
consistent with a similar role for Tie2 during angiogenesis in
adult tissues. However, because global disruption of Tie2 signaling
results in embryonic lethality, establishment of a functional role for
Tie2 signaling during angiogenesis in adult tissues will require the
development of alternative approaches to specifically inhibit Tie2
signaling in vivo.
Role of Tie2 in the Resting Vasculature
Other studies have shown the presence of Tie2 mRNA in adult
tissues; however, these studies did not address the cellular
localization, protein expression, or phosphorylation of
Tie2 in these tissues.8 13 The results of the present
study demonstrating Tie2 protein expression and
phosphorylation in a wide range of adult tissues
suggests a role for Tie2 signaling in the maintenance of the
quiescent adult vasculature. Moreover, the expression of Tie2 in
endothelia of arteries, veins, and capillaries suggests a function for
Tie2 at all levels of the vasculature. Maintenance functions
have been suggested for other endothelial RTKs. For
example, Flt-1, a VEGF receptor, is also broadly expressed in the adult
vasculature.21 Furthermore, prestimulation with VEGF has
been shown to have a protective effect on the
endothelium against ischemic
insult.22 The expression of Flt-1 in the resting
vasculature and the protective effect of VEGF on vascular function
strongly suggest a role for VEGF receptor signaling in vascular
maintenance.
A mutation in the Tie2 kinase domain has been correlated with venous malformations in two unrelated families.23 Histochemical analysis of these venous malformations revealed distended vessels surrounded by disorganized smooth muscle cells, suggesting that Tie2 signaling may be involved in the maintenance of normal vascular architecture by influencing either the phenotypic behavior of endothelial cells or endothelial cell–smooth muscle cell communication. Elucidation of such a role for Tie2 in the resting vasculature will require the development of methods to inhibit Tie2 signaling in the established vasculature.
Tie2 Signaling in the Mature Vasculature
Generally, signaling by RTKs is initiated by ligand-mediated
dimerization and autophosphorylation.24 25 26
In cultured endothelial cells, Tie2
phosphorylation was induced by stimulation with a newly
discovered Tie2 ligand, angiopoietin-1.27 Disruption of
Tie2 signaling via angiopoetin-1 knockout, Tie2 knockout, or a Tie2
dominant-negative approach (to block ligand-mediated
autophosphorylation) all yielded similar
phenotypes.16 17 28 Taken together, these results
suggest that, as is the case for other RTKs, ligand-mediated
autophosphorylation is required for Tie2 signaling.
Thus, the presence of tyrosine-phosphorylated Tie2
during angiogenesis and in the quiescent vasculature is
consistent with ligand-mediated activation of Tie2 and is
indicative of active downstream signaling.
After receptor autophosphorylation, phosphotyrosine
residues serve as binding sites for cytoplasmic signaling molecules. It
is likely that the complement of signaling molecules that associate
with the autophosphorylated receptor dictates the
cellular responses to receptor activation. We have recently shown that
Tie2 associates with the cytoplasmic signaling molecules Grb2 and
SH-PTP2 in a phosphorylation-dependent
manner.29 Grb2 and SH-PTP2 have been shown to be involved
in activation of the Ras/MAP kinase pathway.30 31 32
Activation of the Ras/MAP kinase pathway is known to be involved in a
number of cellular responses, including proliferation. Although
angiopoietin-1 elicited no mitogenic activity in cultured
endothelial cells, Tie2 signaling may be required for
efficient replication of endothelial cells in
vivo.27 Alternatively, Tie2 signaling might influence
other endothelial responses, including adhesion,
differentiation, or survival. A major role for Tie2 in the maturation
and stabilization of the neovasculature might necessitate a somewhat
restricted activation of Tie2 in the early stages of angiogenesis, as
depicted by the apparent decrease of Tie2 receptor
phosphorylation per amount of total receptor in the
early stages of wound healing (Fig 3). Continued progress in the study
of Tie2 function will require further dissection of its downstream
signaling pathways and relating these pathways to specific cellular
responses.
Limitations of the Present Study
By Western blotting and RNase protection assay, it is clear that
Tie2 expression is increased in skin wounds during angiogenesis
compared with normal skin. It is likely that this increase
represents an upregulation of Tie2 expression in the
endothelium of neovessels, resulting in increased
receptor density. However, it is also possible that at least part of
the apparent increase in Tie2 expression is due to the increased
general vascularity of wound tissue compared with normal skin. The
approaches used in the present study cannot fully distinguish
between these two possibilities.
Significance of Tie2 Expression and Phosphorylation
in the Mature Vasculature
Many disease processes are known to be driven by angiogenesis,
including cancer, atherosclerosis, diabetic
retinopathy, and arthritis.33 34 For
instance, tumor growth beyond 2 mm in diameter is constrained by a
requirement for angiogenesis.35 Moreover,
neovascularization of atherosclerotic plaques is likely involved in
plaque progression and plaque rupture leading to vascular occlusion and
myocardial infarction.36 37 38 39 Our results demonstrating Tie2
expression and phosphorylation during angiogenesis in
adult tissues suggest a role for Tie2 signaling in pathological
angiogenesis. Thus, strategies to inhibit Tie2 signaling might yield
useful therapeutic agents for these "angiogenic" diseases.
Although many diseases are driven by vascular growth, others such as coronary artery disease and peripheral vascular disease are characterized by vascular insufficiency. In these diseases, stimulating vascular growth with angiogenic growth factors such as FGF and/or VEGF may help to restore blood flow to ischemic tissues.40 41 42 43 44 45 46 47 Results of the present study suggest that, like VEGF and FGF, Tie ligands might also be useful agents to stimulate revascularization of ischemic tissues. The potential usefulness of Tie ligands for angiogenic therapy will be determined by their ability to stimulate angiogenesis alone or to potentiate the response to other agents in standard angiogenesis assays.
There is mounting evidence from animal studies that both proangiogenic and antiangiogenic therapy might be relatively free of adverse effects. However, enthusiasm for therapeutic strategies perturbing Tie2 and perhaps VEGF receptor function should be tempered by the possible disruption of crucial roles for these receptors in vascular maintenance. Further investigation into the specific signaling pathways used for vascular growth and maintenance may lead to more specific and effective strategies for both proangiogenic and antiangiogenic therapy.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by Duke University Breast Cancer SPORE grant CA-66338 (Drs Peters, Dewhirst, Haroon, and Greenberg) from the National Institutes of Health, a grant from the McDonnell Foundation, and grant RO1 HL-55265 (Drs Peters and Wong) from the National Institutes of Health. Many thanks to Dr David W. Schomberg, Duke University Medical Center, Division of Reproductive Biology, OBGYN, and the Department of Cell Biology for comments on the manuscript and to Conrad Ireland for technical assistance.
Received January 31, 1997; accepted June 27, 1997.
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 A. Otani, H. Takagi, H. Oh, S. Koyama, and Y. Honda Angiotensin II Induces Expression of the Tie2 Receptor Ligand, Angiopoietin-2, in Bovine Retinal Endothelial Cells Diabetes, April 1, 2001; 50(4): 867 - 875. [Abstract] [Full Text]
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M. J. Currie, S. P. Gunningham, C. Han, P. A. E. Scott, B. A. Robinson, A. L. Harris, and S. B. Fox Angiopoietin-1 Is Inversely Related to Thymidine Phosphorylase Expression in Human Breast Cancer, Indicating a Role in Vascular Remodeling Clin. Cancer Res., April 1, 2001; 7(4): 918 - 927. [Abstract] [Full Text]
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M. W. Geraci, M. Moore, T. Gesell, M. E. Yeager, L. Alger, H. Golpon, B. Gao, J. E. Loyd, R. M. Tuder, and N. F. Voelkel Gene Expression Patterns in the Lungs of Patients With Primary Pulmonary Hypertension : A Gene Microarray Analysis Circ. Res., March 30, 2001; 88(6): 555 - 562. [Abstract] [Full Text] [PDF]
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I. Kim, S.-O. Moon, C.-Y. Han, Y. K. Pak, S. K. Moon, J. J. Kim, and G. Y. Koh The angiopoietin-tie2 system in coronary artery endothelium prevents oxidized low-density lipoprotein-induced apoptosis Cardiovasc Res, March 1, 2001; 49(4): 872 - 881. [Abstract] [Full Text] [PDF]
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S. A. Ahmad, W. Liu, Y. D. Jung, F. Fan, M. Wilson, N. Reinmuth, R. M. Shaheen, C. D. Bucana, and L. M. Ellis The Effects of Angiopoietin-1 and -2 on Tumor Growth and Angiogenesis in Human Colon Cancer Cancer Res., February 1, 2001; 61(4): 1255 - 1259. [Abstract] [Full Text]
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Q. Yu and I. Stamenkovic Angiopoietin-2 Is Implicated in the Regulation of Tumor Angiogenesis Am. J. Pathol., February 1, 2001; 158(2): 563 - 570. [Abstract] [Full Text] [PDF]
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S. Fujiyama, H. Matsubara, Y. Nozawa, K. Maruyama, Y. Mori, Y. Tsutsumi, H. Masaki, Y. Uchiyama, Y. Koyama, A. Nose, et al. Angiotensin AT1 and AT2 Receptors Differentially Regulate Angiopoietin-2 and Vascular Endothelial Growth Factor Expression and Angiogenesis by Modulating Heparin Binding-Epidermal Growth Factor (EGF)-Mediated EGF Receptor Transactivation Circ. Res., January 19, 2001; 88(1): 22 - 29. [Abstract] [Full Text] [PDF]
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 H. Ding, L. Roncari, X. Wu, N. Lau, P. Shannon, A. Nagy, and A. Guha Expression and hypoxic regulation of angiopoietins in human astrocytomas Neuro-oncol, January 1, 2001; 3(1): 1 - 10. [Abstract] [PDF]
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H. Beck, T. Acker, C. Wiessner, P. R. Allegrini, and K. H. Plate Expression of Angiopoietin-1, Angiopoietin-2, and Tie Receptors after Middle Cerebral Artery Occlusion in the Rat Am. J. Pathol., November 1, 2000; 157(5): 1473 - 1483. [Abstract] [Full Text] [PDF]
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L. Wyder, A. Vitaliti, H. Schneider, L. W. Hebbard, D. R. Moritz, M. Wittmer, M. Ajmo, and R. Klemenz Increased Expression of H/T-Cadherin in Tumor-penetrating Blood Vessels Cancer Res., September 1, 2000; 60(17): 4682 - 4688. [Abstract] [Full Text]
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C. Willam, P. Koehne, J. S. Jurgensen, M. Grafe, K. D. Wagner, S. Bachmann, U. Frei, and K.-U. Eckardt Tie2 Receptor Expression Is Stimulated by Hypoxia and Proinflammatory Cytokines in Human Endothelial Cells Circ. Res., September 1, 2000; 87(5): 370 - 377. [Abstract] [Full Text] [PDF]
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T. Uchida, M. Nakashima, Y. Hirota, Y. Miyazaki, T. Tsukazaki, and H. Shindo Immunohistochemical localisation of protein tyrosine kinase receptors Tie-1 and Tie-2 in synovial tissue of rheumatoid arthritis: correlation with angiogenesis and synovial proliferation Ann Rheum Dis, August 1, 2000; 59(8): 607 - 614. [Abstract] [Full Text]
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 A. W. Griffioen and G. Molema Angiogenesis: Potentials for Pharmacologic Intervention in the Treatment of Cancer, Cardiovascular Diseases, and Chronic Inflammation Pharmacol. Rev., June 1, 2000; 52(2): 237 - 268. [Abstract] [Full Text] [PDF]
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S. J. Mandriota, C. Pyke, C. Di Sanza, P. Quinodoz, B. Pittet, and M. S. Pepper Hypoxia-Inducible Angiopoietin-2 Expression Is Mimicked by Iodonium Compounds and Occurs in the Rat Brain and Skin in Response to Systemic Hypoxia and Tissue Ischemia Am. J. Pathol., June 1, 2000; 156(6): 2077 - 2089. [Abstract] [Full Text] [PDF]
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K. Hata, R. Fujiwaki, K. Nakayama, M. Fukumoto, and K. Miyazaki Expression of TP and TIE2 genes in normal ovary with corpus luteum and in ovarian cancer: correlation with ultrasound-derived peak systolic velocity Mol. Hum. Reprod., April 1, 2000; 6(4): 319 - 323. [Abstract] [Full Text] [PDF]
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V. EVANS, A. HATZOPOULOS, W. C. AIRD, H. B. RAYBURN, R. D. ROSENBERG, and J. A. KUIVENHOVEN Targeting the Hprt locus in mice reveals differential regulation of Tie2 gene expression in the endothelium Physiol Genomics, March 13, 2000; 2(2): 67 - 75. [Abstract] [Full Text] [PDF]
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N. Jones, Z. Master, J. Jones, D. Bouchard, Y. Gunji, H. Sasaki, R. Daly, K. Alitalo, and D. J. Dumont Identification of Tek/Tie2 Binding Partners. BINDING TO A MULTIFUNCTIONAL DOCKING SITE MEDIATES CELL SURVIVAL AND MIGRATION J. Biol. Chem., October 22, 1999; 274(43): 30896 - 30905. [Abstract] [Full Text] [PDF]
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W. N. Procopio, P. I. Pelavin, W. M. F. Lee, and N. M. Yeilding Angiopoietin-1 and -2 Coiled Coil Domains Mediate Distinct Homo-oligomerization Patterns, but Fibrinogen-like Domains Mediate Ligand Activity J. Biol. Chem., October 15, 1999; 274(42): 30196 - 30201. [Abstract] [Full Text] [PDF]
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A. Otani, H. Takagi, H. Oh, S. Koyama, M. Matsumura, and Y. Honda Expressions of Angiopoietins and Tie2 in Human Choroidal Neovascular Membranes Invest. Ophthalmol. Vis. Sci., August 1, 1999; 40(9): 1912 - 1920. [Abstract] [Full Text] [PDF]
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H. T. YUAN, C. SURI, G. D. YANCOPOULOS, and A. S. WOOLF Expression of Angiopoietin-1, Angiopoietin-2, and the Tie-2 Receptor Tyrosine Kinase during Mouse Kidney Maturation J. Am. Soc. Nephrol., August 1, 1999; 10(8): 1722 - 1736. [Abstract] [Full Text]
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 J. T. Calvert, T. J. Riney, C. D. Kontos, E. H. Cha, V. G. Prieto, C. R. Shea, J. N. Berg, N. C. Nevin, S. A. Simpson, K. A. Pasyk, et al. Allelic and locus heterogeneity in inherited venous malformations Hum. Mol. Genet., July 1, 1999; 8(7): 1279 - 1289. [Abstract] [Full Text] [PDF]
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 J. Holash, P. C. Maisonpierre, D. Compton, P. Boland, C. R. Alexander, D. Zagzag, G. D. Yancopoulos, and S. J. Wiegand Vessel Cooption, Regression, and Growth in Tumors Mediated by Angiopoietins and VEGF Science, June 18, 1999; 284(5422): 1994 - 1998. [Abstract] [Full Text]
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H. Oh, H. Takagi, K. Suzuma, A. Otani, M. Matsumura, and Y. Honda Hypoxia and Vascular Endothelial Growth Factor Selectively Up-regulate Angiopoietin-2 in Bovine Microvascular Endothelial Cells J. Biol. Chem., May 28, 1999; 274(22): 15732 - 15739. [Abstract] [Full Text] [PDF]
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 M. Puri, J Partanen, J Rossant, and A Bernstein Interaction of the TEK and TIE receptor tyrosine kinases during cardiovascular development Development, January 10, 1999; 126(20): 4569 - 4580. [Abstract] [PDF]
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 G. C. Hughes, J. E. Lowe, A. P. Kypson, J. D. St. Louis, A. M. Pippen, K. G. Peters, R. E. Coleman, T. R. DeGrado, C. L. Donovan, B. H. Annex, et al. Neovascularization after transmyocardial laser revascularization in a model of chronic ischemia Ann. Thorac. Surg., December 1, 1998; 66(6): 2029 - 2036. [Abstract] [Full Text] [PDF]
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J. Lauren, Y. Gunji, and K. Alitalo Is Angiopoietin-2 Necessary for the Initiation of Tumor Angiogenesis? Am. J. Pathol., November 1, 1998; 153(5): 1333 - 1339. [Full Text] [PDF]
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A. Stratmann, W. Risau, and K. H. Plate Cell Type-Specific Expression of Angiopoietin-1 and Angiopoietin-2 Suggests a Role in Glioblastoma Angiogenesis Am. J. Pathol., November 1, 1998; 153(5): 1459 - 1466. [Abstract] [Full Text] [PDF]
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W. R. Burfeind Jr, F. G. Duhaylongsod, B. H. Annex, and D. Samuelson High-flow gas insufflation to facilitate MIDCABG: effects on coronary endothelium Ann. Thorac. Surg., October 1, 1998; 66(4): 1246 - 1249. [Abstract] [Full Text] [PDF]
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T. Asahara, D. Chen, T. Takahashi, K. Fujikawa, M. Kearney, M. Magner, G. D. Yancopoulos, and J. M. Isner Tie2 Receptor Ligands, Angiopoietin-1 and Angiopoietin-2, Modulate VEGF-Induced Postnatal Neovascularization Circ. Res., August 10, 1998; 83(3): 233 - 240. [Abstract] [Full Text] [PDF]
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K. G. Peters Vascular Endothelial Growth Factor and the Angiopoietins : Working Together to Build a Better Blood Vessel Circ. Res., August 10, 1998; 83(3): 342 - 343. [Full Text] [PDF]
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P. Lin, J. A. Buxton, A. Acheson, C. Radziejewski, P. C. Maisonpierre, G. D. Yancopoulos, K. M. Channon, L. P. Hale, M. W. Dewhirst, S. E. George, et al. Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2 PNAS, July 21, 1998; 95(15): 8829 - 8834. [Abstract] [Full Text] [PDF]
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C. D. Kontos, T. P. Stauffer, W.-P. Yang, J. D. York, L. Huang, M. A. Blanar, T. Meyer, and K. G. Peters Tyrosine 1101 of Tie2 Is the Major Site of Association of p85 and Is Required for Activation of Phosphatidylinositol 3-Kinase and Akt Mol. Cell. Biol., July 1, 1998; 18(7): 4131 - 4140. [Abstract] [Full Text]
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