共查询到20条相似文献,搜索用时 31 毫秒
1.
Angiogenesis plays an essential role in the growth and dissemination of solid tumor cancers. The expression of endothelial
cell integrin αvβ3 has been shown to increase during vascular proliferation associated with human tumors. Selective antagonists
of αvβ3 can block angiogenesis and tumor growth by inducing programmed cell death in proliferating endothelial cells. Monoclonal
antibody 7E3, an antagonist of the human, but not murine, integrins αvβ3 and αIIbβ3 (GPIIb/IIIa), inhibits platelet aggregation.
It is the parent antibody of a mouse/human chimeric antibody fragment approved for adjunctive therapy of patients undergoing
percutaneous coronary interventions to prevent ischemic complications (c7E3Fab; abciximab; ReoPro). To evaluate the potential
of 7E3 to inhibit human angiogenesis and tumor growth independent of its antiplatelet effects, we established integrin αvβ3-negative
human melanoma tumors in full-thickness human skin grafted onto SCID mice. The resulting tumors induce a human angiogenic
response as assessed by the immunoreactivity of vascular cells with monoclonal antibodies specific for human CD31. Administration
of 7E3 prevented or significantly inhibited the growth of tumors, and this effect correlated with a significant reduction
in the number of blood vessels supplying the tumors. These results support the previous findings that blockade of integrin
αvβ3 inhibits angiogenesis and tumor growth and indicates that dual inhibitors of αvβ3 and αIIbβ3 are effective in blocking
tumor growth and angiogenesis.
This revised version was published online in June 2006 with corrections to the Cover Date. 相似文献
2.
Vanderslice P Munsch CL Rachal E Erichsen D Sughrue KM Truong AN Wygant JN McIntyre BW Eskin SG Tilton RG Polverini PJ 《Angiogenesis》1998,2(3):265-275
Tumor necrosis factor-α (TNF-α) and fibroblast growth factor-2 (FGF-2 or bFGF) are potent stimulators of angiogenesis. TNF-α,
but not FGF-2, can induce the expression of vascular cell adhesion molecule-1 (VCAM-1) on the surface of endothelial cells.
The soluble form of VCAM-1 has recently been demonstrated to function as an angiogenic mediator. Here we demonstrate that
monoclonal antibodies directed against VCAM-1 or its α4 integrin counter-receptor inhibited TNF-α-induced endothelial cell
migration in vitro. Angiogenesis induced in vivo in rat corneas by TNF-α was inhibited by a neutralizing antibody directed
against the rat α4 integrin subunit. A peptide antagonist of the a4 integrins blocked TNF-α-induced endothelial cell migration
in vitro and angiogenesis in rat corneas in vivo. No inhibition by the antibodies or peptide antagonist was observed either
in vitro or in vivo when FGF-2 was used as the stimulus. The peptide antagonist did not inhibit TNF-a binding to its receptor
nor did it block the function of αvβ3, an integrin previously implicated in TNF-a and FGF-2 mediated angiogenesis. These results
demonstrate that angiogenic processes induced by TNF-α are mediated in part by agr;4 integrins possibly by a mechanism involving
the induction of soluble VCAM-1.
This revised version was published online in June 2006 with corrections to the Cover Date. 相似文献
3.
The αvβ3 integrin plays an important role in tumor growth and angiogenesis. Inhibition of this receptor by intact bivalent
antibodies has been shown to inhibit angiogenesis and tumor growth. In this study we tested the chimeric Fab of 7E3 (c7E3
Fab), an antibody reactive with human platelet GPIIb/IIIa and αvβ3 to determine if it would inhibit in vivo angiogenesis and
tumor growth in a SCID mouse/human skin tumor growth and angiogenesis model. c7E3 Fab inhibited human tumor angiogenesis and
tumor growth. These data suggest monovalent antibody fragments devoid of antibody effector function can have efficacy in preclinical
models of angiogenesis. 相似文献
4.
Angiostatin selectively inhibits signaling by hepatocyte growth factor in endothelial and smooth muscle cells 总被引:6,自引:1,他引:6
Angiostatin, an inhibitor of angiogenesis, contains 3 to 4 kringle domains that are derived from proteolytic cleavage of plasminogen. The antiangiogenic effects of angiostatin occur, in part, from its inhibition of endothelial cell surface adenosine triphosphate synthase, integrin functions, and pericellular proteolysis. Angiostatin has structural similarities to hepatocyte growth factor (HGF; "scatter factor"), a promoter of angiogenesis, that induces proliferation and migration of both endothelial and smooth muscle cells via its cell surface receptor, c-met. We hypothesized that angiostatin might block HGF-induced signaling in endothelial and smooth muscle cells. Angiostatin inhibited HGF-induced phosphorylation of c-met, Akt, and ERK1/2. Angiostatin also significantly inhibited proliferation of human umbilical vein endothelial cells (HUVECs) induced by HGF. In contrast, angiostatin did not inhibit vascular endothelial growth factor (VEGF)-or basic fibroblast growth factor (bFGF)-induced signaling events or HUVEC proliferation. Angiostatin bound to immobilized truncated c-met produced by A431 cells and could be immunoprecipitated as a complex with soluble c-met. HGF inhibited the binding of (125)I-angiostatin to HUVECs. Soluble c-met, produced by several tumor cell lines, could inhibit the antiangiogenic effect of angiostatin. The disruption of HGF/c-met signaling is a novel mechanism for the antiangiogenic effect of angiostatin. 相似文献
5.
Down syndrome candidate region 1,a downstream target of VEGF, participates in endothelial cell migration and angiogenesis 总被引:3,自引:0,他引:3
Vascular endothelial growth factor (VEGF) is a principal stimulator of angiogenesis. However, the downstream targets of VEGF in endothelial cells (ECs) are not entirely clarified. Survey of downstream targets of VEGF in human ECs identified a number of genes, including Down syndrome candidate region 1 (DSCR1). Here, we confirmed the inducible expression of DSCR1 in ECs by Northern and Western blottings. Moreover, VEGF-stimulated induction of DSCR1 was blocked by anti-VEGF receptor-2 monoclonal antibody (mAb), or the specific calcineurin inhibitors cyclosporin A and FK506. The expression of DSCR1 in ECs of neovessels was further shown by immunohistochemical analysis. We therefore examined whether DSCR1 played any roles in angiogenesis. The specific downregulation of DSCR1 expression by antisense oligonucleotide (AS-ODN) inhibited VEGF-stimulated migration of ECs as well as angiogenesis in vivo. AS-ODN inhibited the spreading of ECs on vitronectin, as well as on the immobilized anti-alphavbeta3 mAb, but not on anti-alphavbeta5 mAb. Moreover, AS-ODN inhibited tyrosine phosphorylation of focal adhesion kinase when ECs were plated on a vitronectin-coated dish. Immunoprecipitation followed by Western blotting showed the coimmunoprecipitation of DSCR1 and integrin alphavbeta3. These results suggest that DSCR1 is involved in angiogenesis by regulating adhesion and migration of ECs via the interaction with integrin alphavbeta3. 相似文献
6.
Angiogenesis is important for tumor growth and metastasis. CLT1 (CGLIIQKNEC), a peptide that binds to tumor interstitial spaces
in the presence of fibrin-fibronectin, has structural similarity to the anti-angiogenic β-sheet peptides anastellin and anginex.
This similarity is reflected in the ability of CLT1 to form co-aggregates with fibronectin that induce an unfolded protein
response and cause autophagic cell death in proliferating endothelial cells. CLT1 cytotoxicity is mediated at least in parts
by a novel CLT1 binding protein, Chloride Intracellular Channel 1 (CLIC1), which promotes internalization of CLT1-fibronectin
co-aggregates in a mechanism that depends on the LIIQK amino acid sequence of CLT1. LIIQK encompasses amino acid residues
relevant for CLT1 binding to CLIC1 and in addition, facilitates the formation of CLT1-fibronectin co-aggregates, which in
turn promote translocation of CLIC1 to the endothelial cell surface through ligation of integrin αvβ3. Paralleling the in
vitro results, we found that CLT1 co-localizes with CLIC1 and fibronectin in angiogenic blood vessels in vivo, and that CLT1
treatment inhibited angiogenesis and tumor growth. Our findings show that CLT1 is a new anti-angiogenic compound, and its
mechanism of action is to form co-aggregates with fibronectin, which bind to angiogenic endothelial cells through integrins,
become internalized through CLIC1 and elicit a cytotoxic unfolded protein response. The simple structure and high potency
of CLT1 make it a potentially useful compound for anti-angiogenic treatments. 相似文献
7.
Anti-Angiogenic Activity of Contortrostatin, a Disintegrin from Agkistrodon Contortrix Contortrix Snake Venom 总被引:5,自引:0,他引:5
Previous work in our laboratory has shown that contortrostatin (CN), a disintegrin from southern copperhead snake venom, possess anti-angiogenic activity. In the present study we further examined the anti-angiogenic activity of CN, focusing on the mechanisms of CN inhibition of angiogenesis. CN inhibited migration and invasion, and significantly altered Matrigel-induced tube formation of human umbilical vein endothelial cells (HUVEC), but did not affect cell viability, or MMP-2 and MMP-9 activity. Immunocytochemistry of HUVEC revealed that CN disrupted actin cytoskeleton and altered VE-cadherin distribution at cell-cell contacts. CN downregulated focal adhesion kinase (FAK) and paxillin tyrosine phosphorylation in adherent HUVEC. There was also significant inhibition of angiogenesis in vivo by CN as assessed by implanting Matrigel plugs in C57 mice and measuring ingrowth of blood vessels using either factor VIII staining or hemoglobin determination. In conclusion, the present findings confirm our earlier studies and demonstrate conclusively that CN possess strong anti-angiogenic activity in vitro and in vivo. 相似文献
8.
9.
10.
Disruption of matrix metalloproteinase 2 binding to integrin alpha vbeta 3 by an organic molecule inhibits angiogenesis and tumor growth in vivo 总被引:10,自引:0,他引:10
下载免费PDF全文
![点击此处可从《Proceedings of the National Academy of Sciences of the United States of America》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Silletti S Kessler T Goldberg J Boger DL Cheresh DA 《Proceedings of the National Academy of Sciences of the United States of America》2001,98(1):119-124
Matrix metalloproteinase 2 (MMP2) can associate with integrin alpha(v)beta3 on the surface of endothelial cells, thereby promoting vascular invasion. Here, we describe an organic molecule (TSRI265) selected for its ability to bind to integrin alphav(v)beta3 and block alpha(v)beta3 interaction with MMP2. Although disrupting alpha(v)beta3/MMP2 complex formation, TSRI265 has no effect on alpha(v)beta3 binding to its extracellular matrix ligand vitronectin and does not influence MMP2 activation or catalytic activity directly. However, TSRI265 acts as a potent antiangiogenic agent and thereby blocks tumor growth in vivo. These findings suggest that activated MMP2 does not facilitate vascular invasion during angiogenesis unless it forms a complex with alpha(v)beta(3) on the endothelial cell surface. By disrupting endothelial cell invasion without broadly suppressing cell adhesion or MMP function, the use of compounds such as TSRI265 may provide a novel therapeutic approach for diseases associated with uncontrolled angiogenesis. 相似文献
11.
Su X Mi J Yan J Flevaris P Lu Y Liu H Ruan Z Wang X Kieffer N Chen S Du X Xi X 《Blood》2008,112(3):592-602
Mutational analysis has established that the cytoplasmic tail of the integrin β3 subunit binds c-Src (termed as Src in this study) and is critical for bidirectional integrin signaling. Here we show in washed human platelets that a cell-permeable, myristoylated RGT peptide (myr-RGT) corresponding to the integrin β3 C-terminal sequence dose-dependently inhibited stable platelet adhesion and spreading on immobilized fibrinogen, and fibrin clot retraction as well. Myr-RGT also inhibited the aggregation-dependent platelet secretion and secretion-dependent second wave of platelet aggregation induced by adenosine diphosphate, ristocetin, or thrombin. Thus, myr-RGT inhibited integrin outside-in signaling. In contrast, myr-RGT had no inhibitory effect on adenosine diphosphate-induced soluble fibrinogen binding to platelets that is dependent on integrin inside-out signaling. Furthermore, the RGT peptide induced dissociation of Src from integrin β3 and dose-dependently inhibited the purified recombinant β3 cytoplasmic domain binding to Src-SH3. In addition, phosphorylation of the β3 cytoplasmic tyrosines, Y747 and Y759, was inhibited by myr-RGT. These data indicate an important role for β3-Src interaction in outside-in signaling. Thus, in intact human platelets, disruption of the association of Src with β3 and selective blockade of integrin IIbβ3 outside-in signaling by myr-RGT suggest a potential new antithrombotic strategy. 相似文献
12.
Nancy Laurens Marten A. Engelse Clarissa Jungerius Clemens W. Löwik Victor W. M. van Hinsbergh Pieter Koolwijk 《Angiogenesis》2009,12(3):275-285
The fibrinous exudate of a wound or tumor stroma facilitates angiogenesis. We studied the involvement of RGD-binding integrins
during tube formation in human plasma-derived fibrin clots and human purified fibrin matrices. Capillary-like tube formation
by human microvascular endothelial cells in a 3D plasma-derived fibrinous matrix was induced by FGF-2 and TNF-α and depended
largely on cell-bound u-PA and plasmin activities. While tube formation was minimally affected by the addition of either the
αvβ3-integrin inhibiting mAb LM609 or the α5-integrin inhibiting mAb IIA1, the general RGD-antagonist echistatin completely
inhibited this process. Remarkably, when αvβ3- and α5β1-integrins were inhibited simultaneously, tube formation was reduced
by 78%. It was accompanied by a 44% reduction of u-PA antigen accumulation and 41% less production of fibrin degradation products.
αvβ5-integrin-blocking antibodies further enhanced the inhibition by mAb LM609 and mAb IIA1 to 94%, but had no effect by themselves.
αv-specific cRGD only inhibited angiogenesis when α5β1-integrin was simultaneously blocked. Endostatin mimicked the effect
of α5β1-integrin and inhibited tube formation only in the presence of LM609 or cRGD (73 and 80%, respectively). Comparable
results were obtained when purified fibrin matrices were used instead of the plasma-derived fibrinous matrices. These data
show that blocking of tube formation in a fibrinous exudate requires the simultaneous inhibition of αvβ3- and α5β1-integrins.
This may bear impact on attempts to influence angiogenesis in a fibrinous environment. 相似文献
13.
14.
When human umbilical vein endothelial cells (HUVEC) differentiate into capillary-like tubes, there is a five-fold upregulation
of the mRNA for thymosin β4 (Tβ4) (Grant et al. J Cell Sci 1995; 108: 3685–94 [1]) and this endogenous expression plays an
important role in endothelial cell attachment to and spreading on matrix components. We now show that exogenous addition of
thymosin β4 (in the ng–μg range) to HUVEC in culture can induce several biological responses. These responses include increased
tube formation in vitro. Additionally, exogenous thymosin β4 enhances vascular sprouting in the coronary artery ring angiogenesis assay. Measurements
of these vascular sprouts show a doubling of the vessel area (via increased branching) with as little as 100 ng of synthetic
thymosin β4. These processes appear to involve the binding of thymosin β4 to an unknown cell surface receptor and internalization
of the protein. This cell surface-binding appears not to be mediated through the thymosin β4-actin binding domain LKTET. An
increase in thymosin β4 cytoplasmic staining in HUVEC exposed 10 μg of the peptide appears to occur without increased mRNA
translation. In summary Tβ4 induces an increase in cell-matrix attachment, proliferation, tube formation, internalization
of the peptide and rearrangement of the actin cytoskeleton. The data now defines both an autocrine and paracrine role for
thymosin β4 in vessel formation.
This revised version was published online in June 2006 with corrections to the Cover Date. 相似文献
15.
目的:探讨在与整合素αv复合的模式下,整合素β3亚基胞浆段序列在肿瘤细胞的黏附、伸展和迁移中所起的作用,从而为寻找干扰肿瘤进展的分子靶点提供思路。方法:利用中国仓鼠卵巢(CHO)细胞模型,建立共表达整合素αv与整合素β3全长及其T758、Y759位截短体的稳定细胞株,检测各稳定细胞株在固相化的αvβ3配体玻璃黏连蛋白上的黏附、伸展功能,运用transwell观察各细胞株的迁移能力。结果:稳定表达整合素αvβ3全长的CHO细胞具有在固相化玻璃黏连蛋白上的黏附、伸展和迁移能力。相较于CHO-αvβ3全长细胞株,CHO-αvβ3△758截短体细胞株的黏附、伸展以及迁移能力均明显受损;而CHO-αvβ3△759截短体细胞株仍保留着黏附能力,但伸展能力减弱,并且迁移能力受损明显。结论:整合素β3胞浆尾端YRGT和RGT氨基酸序列在αvβ3介导的细胞黏附和迁移方面发挥不同的作用,提示β3亚基胞内段参与调控肿瘤细胞的重要细胞行为,是潜在的肿瘤治疗靶点。 相似文献
16.
G. E. Rainger Marie-Paule Wautier Gerard Nash & Jean-Luc Wautier 《British journal of haematology》1995,92(1):192-199
We investigated the hypothesis that the infiltration of monocytes into inflamed tissue or damaged vessels would induce a secondary accumulation of neutrophils. Confluent human umbilical vein endothelial cells (HUVEC) and blood monocytes (0.5 or 0.05 monocytes/endothelial cell) were co-incubated for 4 or 24 h. The adhesion of neutrophils flowing over HUVEC was then analysed by video microscopy. Co-incubation caused up to a 40-fold increase in neutrophil adhesion, dependent upon monocyte/HUVEC ratio and duration of incubation. At the lower monocyte/HUVEC ratio, rolling adhesion alone was induced after 4 h co-incubation; however, the full repertoire of rolling, immobilization and migration of neutrophils was observed at all other combinations of co-culture ratio and exposure time. After maximal stimulation by monocytes, antibody blockade of the neutrophil integrin CD18 inhibited neutrophil arrest and migration and revealed underlying rolling adhesion. Rolling was supported by endothelial E-selectin as demonstrated by the almost total abolition of adhesion by a blocking antibody. In a direct comparison, monocytes, tumour necrosis factor α (TNF-α) and interleukin-1β (IL-1β) were assessed for their ability to induce endothelial expression of E-selectin. E selectin was significantly increased by all agents at 4 h, but monocytes alone were able to maintain high levels of E-selectin expression for 24 h. We conclude that monocytes can induce prolonged neutrophil adhesion and migration by activating endothelial cells and causing expression of E-selectin. 相似文献
17.
Aggretin, a snake venom-derived endothelial integrin alpha 2 beta 1 agonist, induces angiogenesis via expression of vascular endothelial growth factor
下载免费PDF全文
![点击此处可从《Blood》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Aggretin, a collagen-like alpha 2 beta 1 agonist purified from Calloselasma rhodostoma venom, was shown to increase human umbilical vein endothelial cell (HUVEC) proliferation and HUVEC migration toward immobilized aggretin was also increased. These effects were blocked by A2-IIE10, an antibody raised against integrin alpha 2. Aggretin bound to HUVECs in a dose-dependent and saturable manner, which was specifically inhibited by A2-IIE10, as examined by flow cytometry. Aggretin elicited significant angiogenic effects in both in vivo and in vitro angiogenesis assays, and incubation of HUVECs with aggretin activated phosphatidylinositol 3-kinase (PI3K), Akt, and extracellular-regulated kinase 1/2 (ERK1/2); these effects were blocked by A2-IIE10 or vascular endothelial growth factor (VEGF) monoclonal antibody (mAb). The angiogenic effect induced by aggretin may be via the production of VEGF because the VEGF level was elevated and VEGF mAb pretreatment inhibited Akt/ERK1/2 activation as well as the in vivo angiogenesis induced by aggretin. The VEGF production induced by aggretin can be blocked by A2-IIE10 mAb pretreatment. In conclusion, aggretin induces endothelial cell proliferation, migration, and angiogenesis by interacting with integrin alpha 2 beta 1 leading to activation of PI3K, Akt, and ERK1/2 pathways, and the increased expression of VEGF may be responsible for its angiogenic activity. 相似文献
18.
Erythropoietin (EPO) and thrombopoietin (c-MPL ligand; TPO) are structurally similar cytokines and support respectively,
the proliferation and differentiation for erythroid and megakaryocytic lineages, as well as more primitive progenitors. We
studied the effect of these cytokines on the induction of adhesion of human growth-factor-dependent hematopoietic cells to
immobilized fibronectin, which is a main component of the extracellular matrix in the bone marrow. MO7ER cells that are genetically
engineered to express human EPO receptor and MO7e cells that express endogenous c-MPL were used. Stimulation with either TPO
or EPO induced rapid increases in adhesion of M07ER cells to fibronectin without apparent change of expression of integrins.
Experiments with inhibitory monoclonal antibodies (mAbs) demonstrated that CD41, which has been reported to be involved in
TPO-induced adhesion of megakaryocytic cells, is not responsible for this enhanced adhesion. Anti-β1 integrin mAb inhibited
adhesion completely, while inhibition by anti-α4 integrin mAb and anti-α5 integrin mAb was partial. Combination of anti-α4
mAb plus anti-α5 mAb completely abolished adhesion, as did anti-β1 mAb, suggesting that the adhesion is mediated by both α4β1
and α5β1 integrins. Experiments using inhibitors suggested that ligand binding followed by activation of intracellular tyrosine
kinases along with PI3-kinase activation is required. After stimulation of M07ER cells with either TPO or EPO, fibronectin-attached
cells, but not cells in suspension, showed tyrosine phosphorylation of focal adhesion kinase, which plays a central role in
integrin-mediated signaling. These data suggest that TPO and EPO might be involved in homing/migration to the bone marrow
microenvironment by hematopoietic cells that express corresponding receptors.
Received: 3 June 1997 / Accepted: 27 August 1997 相似文献
19.
Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by alpha v beta 3 and alpha 5 beta 1 integrins 总被引:17,自引:0,他引:17
下载免费PDF全文
![点击此处可从《Proceedings of the National Academy of Sciences of the United States of America》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Sudhakar A Sugimoto H Yang C Lively J Zeisberg M Kalluri R 《Proceedings of the National Academy of Sciences of the United States of America》2003,100(8):4766-4771
Tumstatin and endostatin are two inhibitors of angiogenesis derived from precursor human collagen molecules known as alpha 3 chain of type IV collagen and alpha1 chain of type XVIII collagen, respectively. Although both these inhibitors are noncollagenous (NC1) domain fragments of collagens, they only share a 14% amino acid homology. In the present study we evaluated the functional receptors, mechanism of action, and intracellular signaling induced by these two collagen-derived inhibitors. Human tumstatin prevents angiogenesis via inhibition of endothelial cell proliferation and promotion of apoptosis with no effect on migration, whereas human endostatin prevents endothelial cell migration with no effect on proliferation. We demonstrate that human tumstatin binds to alpha v beta 3 integrin in a vitronectin/fibronectin/RGD cyclic peptide independent manner, whereas human endostatin competes with fibronectin/RGD cyclic peptide to bind alpha 5 beta 1 integrin. The activity of human tumstatin is mediated by alpha v beta 3 integrin, whereas the activity of human endostatin is mediated by alpha 5 beta 1 integrin. Additionally, although human tumstatin binding to alpha v beta 3 integrin leads to the inhibition of Cap-dependent translation (protein synthesis) mediated by focal adhesion kinase/phosphatidylinositol 3-kinase/Akt/mTOR/4E-BP1 pathway, human endostatin binding to alpha 5 beta 1 integrin leads to the inhibition of focal adhesion kinase/c-Raf/MEK1/2/p38/ERK1 mitogen-activated protein kinase pathway, with no effect on phosphatidylinositol 3-kinase/Akt/mTOR/4E-BP1 and Cap-dependent translation. Collectively, such distinct properties of human tumstatin and human endostatin provide the first insight into their diverse antiangiogenic actions and argue for combining them for targeting tumor angiogenesis. 相似文献
20.
Cytoskeletal changes induced by excess extracellular matrix impair endothelial cell replication 总被引:2,自引:0,他引:2
Summary Thickening of basement membranes is an early and characteristic feature of diabetic vessels, but its consequences on the
properties of vascular cells remain undefined. We investigated whether and how excess extracellular matrix (ECM) alters the
replication of vascular endothelial cells in vitro. To test the effects of endogenous excess matrix, human umbilical vein
endothelial cells (HUVEC) were plated on ECM produced under culture conditions (high ambient glucose) that increase ECM synthesis.
Four of six HUVEC isolates plated on such ECM yielded a lower cell number (68 ± 18 %) than cells plated on control ECM. Growth
inhibition was observed in HUVEC cultured on elevated concentrations (10 and 50 μg/ml) of exogenous fibronectin, when compared
with HUVEC plated on tissue culture plastic or 0.25, 1.0, and 5.0 μg/ml fibronectin; the decreased replication was attributable
to delayed transit through the G1 phase of the cell cycle. HUVEC grown on both 1 and 10 μg/ml fibronectin exhibited a modest upregulation of the fibronectin-specific
integrin receptor α5β1, and increased attachment to fibronectin substratum. However, unique to the HUVEC plated on growth-inhibitory concentrations
of fibronectin was a redistribution in situ of integrins and vinculin to form more numerous focal adhesions, and an increased
polymerization of cytoskeletal actin to form stress fibers. Concentrations (0.01 μg/ml) of cytochalasin D intended to prevent
excess actin polymerization prevented the growth inhibition. Thus, excess ECM hampers endothelial cell replication in vitro
through increased cell-ECM adhesion and attendant cytoskeletal rearrangements. These phenotypic changes provide probes to
test whether cell-ECM interactions are altered in diabetic vessels in a direction that may compromise orderly endothelial
cell renewal and its antithrombogenic function. [Diabetologia (1997) 40: 879–886]
Received: 14 January 1997 and in revised form: 2 April 1997 相似文献