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Results for “Integrin alphaVbeta3”

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At least 19 recordsLinked to original sources

PubMed2004

Regulation of macrophage foam cell formation by alphaVbeta3 integrin: potential role in human atherosclerosis.

The accumulation of macrophage foam cells in atherosclerotic lesions is associated with both initiation and progression of this disease. Scavenger receptors CD36 and SRA are the primary receptors responsible for conversion of macrophages into foam cells. Integrin alphaVbeta3 plays a role in the differentiation of several cell types, but its involvement in the transition of macrophages into foam cells and the potential role of this receptor in atherosclerosis have not been examined. Using an in vitro model of single surface receptor activation by binding with an immobilized monoclonal antibody specific to alphaVbeta3 integrin we show that ligation of alphaVbeta3 integrin prevents differentiation of blood monocytes and macrophages into the foam cell phenotype via coordinate down-regulation of CD36 and SRA. This effect of alphaVbeta3 integrin ligation can be reproduced by contact with endothelial cells, whereas the inhibition of alphaVbeta3 receptor ligation restores the uptake of oxidized low-density lipoprotein. Moreover, we found that alphaVbeta3 integrin is readily detected in situ on macrophages in early and advanced atherosclerotic lesions and that in vitro exposure to oxidized low-density lipoprotein up-regulates alphaVbeta3 integrin expression. We hypothesize that alphaVbeta3 integrin regulates macrophage functional maturation into foam cells in a persistent manner, and therefore, by targeting alphaVbeta3 receptor it could potentially be possible to regulate progression of atherosclerosis in humans.

Adult↗

PubMed2001

Expression of integrin alphavbeta3 in pig, dog and cattle.

The alphavbeta3 integrin, also known as vitronectin receptor, is an adhesive glycoprotein that promotes angiogenesis in the embryo and tumors such as melanoma. Integrin alphavbeta3 is one of the receptors for adenovirus and hantavirus. There is little information on the constitutive expression of this integrin especially in animal species that are used for biomedical research. We used light and electron microscope immunocytochemistry and western blots to determine integrin alphavbeta3 expression in seven organs in the pig, dog and cattle. Immunohistology showed the integrin expression on the epithelium of small intestine, bile duct and renal proximal convoluted tubules in three species. The airway epithelium revealed a weak reaction for integrin alphavbeta3. Skin showed the integrin in occasional extravascular cells while skeletal muscles were negative. The integrin was expressed only in bronchial vasculature in the lung and occasional dermal microvessels. Many mononuclear cells in the lung and spleen stained for integrin alphavbeta3. Immunogold electron microscopy revealed the expression on the epithelium but not on the vasculature of the small intestine. Western blots detected integrin alphavbeta3 in small intestine and lung but not in skeletal muscles. We conclude the integrin is expressed on the epithelium but not in the vasculature. The expression differs strikingly among organs in the same species although the inter-species differences are minor. Restriction of the integrin to absorptive epithelia of small intestine and kidney may suggest its putative role in endocytosis. Because the integrin is a receptor for adenovirus, these data may be relevant to gene therapy studies.

Animals↗

PubMed1999

Subversion of monocyte functions by coxiella burnetii: impairment of the cross-talk between alphavbeta3 integrin and CR3.

Several intracellular pathogens exploit macrophages as a niche for survival and replication. The success of this strategy requires the subversion or the avoidance of microbicidal functions of macrophages. Coxiella burnetii, the agent of Q fever, is a strictly intracellular bacterium that multiplies in myeloid cells. The survival of C. burnetii may depend on the selective use of macrophage receptors. Virulent C. burnetii organisms were poorly internalized but survived successfully in human monocytes, whereas avirulent variants were efficiently phagocytosed but were also rapidly eliminated. The uptake of avirulent organisms was mediated by leukocyte response integrin (alphavbeta3 integrin) and CR3 (alphaMbeta2 integrin), as demonstrated by using specific Abs and RGD sequence-containing peptides. The phagocytic efficiency of CR3 depends on its activation via alphavbeta3 integrin and integrin-associated protein. Indeed, CR3-mediated phagocytosis of avirulent C. burnetii was abrogated in macrophages from integrin-associated protein-/- mice. In contrast, the internalization of virulent C. burnetii organisms involved the engagement of alphavbeta3 integrin but not that of CR3. The pretreatment of monocytes with virulent C. burnetii organisms prevented the CR3-mediated phagocytosis of zymosan particles and CR3 activation assessed by the expression of the 24 neo-epitope. We conclude that the virulence of C. burnetii is associated with the engagement of alphavbeta3 integrin and the impairment of CR3 activity, which probably results from uncoupling alphavbeta3 integrin from integrin-associated protein. This study describes a strategy not previously reported of phagocytosis modulation by intracellular pathogens.

Antigens, CD↗

PubMed2000

Autologous platelet-derived wound healing factor promotes angiogenesis via alphavbeta3-integrin expression in chronic wounds.

Healing of venous leg ulcers depends on the adhesive interaction and formation of new vascular cells. Angiogenesis on the surface of angiogenic blood vessels requires the vascular integrin alphavbeta3 also known as the vitronectin receptor. Autologous platelet-derived wound healing factor (autologous PDWHF) has been described to regulate the wound healing process by forming granulation tissue in the early healing phase. Here we analysed the influence of autologous PDWHF on the expression of the alphavbeta3 integrin in tissue specimen of venous leg ulcers in comparison with placebo treated controls by using reverse transcriptase-polymerase chain reaction and immunohistochemistry. Our investigations provide evidence that mRNA and protein expression of alphavbeta3 were significantly increased in healing venous leg ulcers after 96 h treatment (p<0.05), whereas the total amount of alphavbeta3 mRNA and protein was not altered in placebo treated patients. In healing leg ulcers the alphavbeta3 integrin was predominantly localized around capillary vessels preferentially at sites of newly formed granulation tissue. Placebo controlled patients displayed no altered expression of the alphavbeta3 integrin in biopsy specimen. These findings suggest that topical autologous platelet-derived wound healing factor influences the process of angiogenesis/revascularization via alphavbeta3 integrin-expression hereby promoting granulation tissue formation in healing leg ulcers.

Aged↗

PubMed2006

Integrin alphaVbeta3 contains a receptor site for resveratrol.

Resveratrol is a naturally occurring polyphenol, which causes apoptosis in cultured cancer cells. We describe a cell surface resveratrol receptor on the extracellular domain of hetero-dimeric alphaVbeta3 integrin in MCF-7 human breast cancer cells. This receptor is linked to induction by resveratrol of extracellular-regulated kinases 1 and 2 (ERK1/2)- and serine-15-p53-dependent phosphorylation leading to apoptosis. The integrin receptor is near the Arg-Gly-Asp (RGD) recognition site on the integrin; an integrin-binding RGD peptide inhibits induction by resveratrol of ERK1/2- and p53-dependent apoptosis. Antibody (Ab) to integrin alphaVbeta3, but not to alphaVbeta5, inhibits activation by resveratrol of ERK1/2 and p53 and consequent apoptosis in estrogen receptor-alpha (ERalpha) positive MCF-7, and ERalpha-negative MDA-MB231 cells. Resveratrol is displaced from the purified integrin by an RGD, but not RGE, peptide, and by alphaVbeta3 integrin-specific Ab. Resveratrol action is blocked by siRNAbeta3, but not by siRNAalphaV. [14C]-Resveratrol binds to commercially purified integrin alphaVbeta3 and to alphaVbeta3 prepared from MCF-7 cells; binding of [14C]-resveratrol to the beta3, but not to the alphaV monomer, is displaced by unlabeled resveratrol. In conclusion, binding of resveratrol to integrin alphaVbeta3, principally to the beta3 monomer, is essential for transduction of the stilbene signal into p53-dependent apoptosis of breast cancer cells.

Apoptosis↗

PubMed2004

Haemangiomas are formed by cells expressing high levels of alphavbeta3 integrin and lacking acetylated LDL uptake.

Haemangiomas are benign tumours occurring in up to 12% of Caucasians, particularly in infancy and childhood. In the present study, two variant cell lines were isolated from murine endothelioma cells. One variant, named t.End.1V(high), represented 16.9% of the parental cell population and was selected by virtue of high expression levels of integrin alphavbeta3 and reduced capacity to endocytose acetylated low-density lipoproteins (Ac-LDLs). A second variant, named t.End.1V(low), represented 38.8% of the parental endothelioma cell line, expressed low levels of alphavbeta3 integrin, and was able to endocytose Ac-LDL. These phenotypic modifications were stable and correlated with specific morphological and functional properties of the two variant cell lines. While the t.End.1V(high) cells induced the formation of large haemangiomas when injected subcutaneously into mice, the t.End.1V(low) cells formed haemangiocytomas. When compared with t.End.1V(low) cells, the t.End.1V(high) cells showed increased migratory capacity, lacked an inflammatory response, and formed cord-like structures in fibrin gels. In contrast, the t.End.1V(low) cells organized into cysts with a lumen in fibrin gels. They rarely formed blood-filled haemangiomas in vivo and recruited host smooth muscle cells, a phenomenon typical for vessel wall maturation of resting cells. These data suggest that Ac-LDL uptake and the level of alphavbeta3 integrin expression are linked to the ability of endothelial cells to form large haemangiomas in vivo.

Animals↗

PubMed2004

Interaction between insulin-like growth factor-I receptor and alphaVbeta3 integrin linked signaling pathways: cellular responses to changes in multiple signaling inputs.

Integrins are heterodimeric transmembrane proteins that mediate cell attachment to extracellular matrix, migration, division, and inhibition of apoptosis. Because growth factors are also important for these processes, there has been interest in cooperative signaling between growth factor receptors and integrins. IGF-I is an important growth factor for vascular cells. One integrin, alphaVbeta3, that is expressed in smooth muscle cells modulates IGF-I actions. Ligand occupancy of alphaVbeta3 is required for IGF-I to stimulate cell migration and division. Src homology 2 containing tyrosine phosphatase (SHP-2) is a tyrosine phosphatase whose recruitment to signaling molecules is stimulated by growth factors including IGF-I. If alphaVbeta3 ligand occupancy is inhibited, there is no recruitment of SHP-2 to alphaVbeta3 and its transfer to downstream signaling molecules is blocked. Ligand occupancy of alphaVbeta3 stimulates tyrosine phosphorylation of the beta3-subunit, resulting in recruitment of SHP-2. This transfer is mediated by an insulin receptor substrate-1-related protein termed DOK-1. Subsequently, SHP-2 is transferred to another transmembrane protein, SHPS-1. This transfer requires IGF-I receptor-mediated tyrosine phosphorylation of SHPS-1, which contains two YXXL motifs that mediate SHP-2 binding. The transfer of SHP-2 to SHPS-1 is also required for recruitment of Shc to SHPS-1. Ligand occupancy of alphaVbeta3 results in sustained Shc phosphorylation and enhanced Shc recruitment. Shc activation results in induction of MAPK. Inhibition of the Shc/SHPS-1 complex formation results in failure to achieve sustained MAPK activation and an attenuated mitogenic response. Thus, within the vessel wall, a mechanism exists whereby ligand occupancy of the alphaVbeta3 integrin is required for assembly of a multicomponent membrane signaling complex that is necessary for cells to respond optimally to IGF-I.

Animals↗

PubMed2005

Noninvasive visualization of the activated alphavbeta3 integrin in cancer patients by positron emission tomography and [18F]Galacto-RGD.

BACKGROUND: The integrin alphavbeta3 plays an important role in angiogenesis and tumor cell metastasis, and is currently being evaluated as a target for new therapeutic approaches. Several techniques are being studied to enable noninvasive determination of alphavbeta3 expression. We developed [(18)F]Galacto-RGD, a (18)F-labeled glycosylated alphavbeta3 antagonist, allowing monitoring of alphavbeta3 expression with positron emission tomography (PET). METHODS AND FINDINGS: Here we show by quantitative analysis of images resulting from a small-animal PET scanner that uptake of [(18)F]Galacto-RGD in the tumor correlates with alphavbeta3 expression subsequently determined by Western blot analyses. Moreover, using the A431 human squamous cell carcinoma model we demonstrate that this approach is sensitive enough to visualize alphavbeta3 expression resulting exclusively from the tumor vasculature. Most important, this study shows, that [(18)F]Galacto-RGD with PET enables noninvasive quantitative assessment of the alphavbeta3 expression pattern on tumor and endothelial cells in patients with malignant tumors. CONCLUSIONS: Molecular imaging with [(18)F]Galacto-RGD and PET can provide important information for planning and monitoring anti-angiogenic therapies targeting the alphavbeta3 integrins and can reveal the involvement and role of this integrin in metastatic and angiogenic processes in various diseases.

Animals↗

PubMed2006

Insulin-like growth factor-I promotes migration in human androgen-independent prostate cancer cells via the alphavbeta3 integrin and PI3-K/Akt signaling.

In its phase of androgen-independence, prostate carcinoma is characterized by a high proliferation rate and by a strong ability to give rise to metastases. IGF-I has been shown to exert a potent mitogenic action on prostate cancer. We investigated whether IGF-I might also affect the motility of prostate cancer cells and defined the mechanism of action. We found that IGF-I promotes the migratory capacity of androgen-independent prostate cancer cells through the activation of its specific receptor, IGF-IR. This effect was accompanied by a change in cell morphology (as revealed by scanning electron microscopy), and by a rearrangement of the actin cytoskeleton. The treatment of cells with the PI3-K inhibitor, LY294002, counteracted the pro-migratory activity of IGF-I. Experiments were then performed to clarify whether the integrin, alphavbeta3, could be involved in the action of IGF-I. We demonstrated that: a) the IGF-I-induced migration of cells is completely antagonized by an antibody specifically blocking the function of alphavbeta3; b) IGF-I increases alphavbeta3 immunofluorescence at the level of cell membranes, and this effect is counteracted by LY294002; and c) IGF-I increases alphavbeta3 protein levels. Our results demonstrate that IGF-I promotes the motility of androgen-independent prostate cancer cells by modulating alphavbeta3 integrin activation/expression; these effects are mediated by the PI3-K/Akt signaling pathway. This study: a) supports a crucial role for IGF-I in the progression of the pathology towards the highly metastatic phase; and b) provides an additional rationale basis for the development of therapeutic strategies directed at the IGF-I/IGF-IR system in the treatment of androgen-independent prostate cancer.

Actins↗

PubMed2004

Increased adenoviral transduction efficacy in human laryngeal carcinoma cells resistant to cisplatin is associated with increased expression of integrin alphavbeta3 and coxsackie adenovirus receptor.

In our study, we investigated molecular mechanisms of increased adenoviral transduction efficacy in cisplatin-resistant human laryngeal carcinoma cells CA3ST as compared to parental cells HEp2. Using reverse transcription-PCR, the genes potentially implicated in adenoviral entry were screened. In cisplatin-resistant cells, only upregulation of alphavbeta3 integrin was detected, which was additionally confirmed by flow cytometry. Moderately increased expression of CAR was determined in cisplatin-resistant CA3ST cells using flow cytometry and measurement of wild-type adenovirus Ad5CMVbetagal attachment. In order to test the implication of alphavbeta3 integrin in transduction efficacy, 6 HEp2-derived alphavbeta3-expressing clones with graded expression of alphavbeta3 were isolated. To a certain degree of density, expression of alphavbeta3 positively correlated with Ad5CMVbetagal transduction efficacy (i.e., increased viral transduction), suggesting a role of alphavbeta3 in transduction efficacy. However, HEp2 clones with the highest alphavbeta3) expression were negatively correlated with transduction efficacy (i.e., decreased viral transduction). This was shown to be associated with downregulation of alphavbeta5 integrin, also involved in viral transduction, in clones with the highest alphavbeta3 expression. The implication of CAR in increased adenoviral transduction efficacy in cisplatin resistant CA3ST cells was further assessed by transduction experiments using adenoviral mutant Ad5FbDelta639 whose entry is only to a very small extent dependent on the presence of CAR. Indeed, Ad5FbDelta639 infected 2.5-fold more, in comparison to wild-type adenovirus, which infected 5-fold more efficiently resistant CA3ST cells than parental HEp2 cells, indicating that increased expression of CAR contributes to increased efficacy of adenoviral transduction. Thus, the data presented provide evidence that both alphavbeta3 integrin and CAR are involved in increased adenoviral transduction efficacy in cisplatin resistant CA3ST cells. These findings may have significant implications in human gene therapy using adenoviruses, especially in patients after unsuccessful cisplatin treatment.

Adenoviridae↗

PubMed2005

Parallel expression of alphaIIbbeta3 and alphavbeta3 integrins in human melanoma cells upregulates bFGF expression and promotes their angiogenic phenotype.

Previous studies indicated that transfection of the platelet integrin alphaIIbbeta3 into human melanoma cells expressing integrin alphavbeta3 promoted their in vivo (but not in vitro) growth and cell survival. To reveal the underlying pathomechanism, we have analyzed the angiogenic phenotype of alphaIIbbeta3 integrin-transduced human melanoma cells expressing integrin alphavbeta3. Upon heterotopic or orthotopic (intracutaneous) injections into SCID mice, the alphaIIbbeta3 integrin-overexpressing clones, ESL, ESH, 19L and 19H, grew more rapidly than the mock transfectant (alphavbeta3 expressing) clone, 3.1P. Morphometry demonstrated an increased intratumoral microvessel density in 19L and 19H tumors compared to 3.1P. Immunocytochemistry and flow cytometry indicated that vascular endothelial growth factor (VEGF) is constitutively expressed in the majority of the cells of both the mock and the alphaIIbbeta3 integrin-transfected clones. However, the mock transfectant clone, 3.1P, did not express basic fibroblast growth factor (bFGF) at protein level (<1%), unlike the alphaIIbbeta3 integrin-transfected clones, 19L and 19H, (33.9 and 84.1%, respectively). Quantitative PCR analysis of 6 related human melanoma clones with various levels of alphaIIbbeta3 integrin expressions revealed a correlation between the alphaIIb protein and bFGF mRNA expressions. Furthermore, cDNA microarray analysis of the 19H cells revealed 12 downregulated and 36 upregulated genes [among them 3 upregulated vasculogenic mimicry-genes (CD34, endothelin receptor B, Prostaglandin I-2 synthase)] when compared to 3.1P cells. The altered bFGF expression may be influenced by integrin-linked signaling, since bbeta3-endonexin is upregulated in alphaIIbbeta3-transfected cells and tyrosine kinase inhibitors downregulate bFGF both at mRNA and protein levels. We propose here that the illegitimate expression of alphaIIbbeta3 integrin in human melanoma cells already expressing alphavbeta3 integrin may alter their in vivo growth properties due to the modulation of their angiogenic phenotype.

Animals↗

PubMed2003

Reduced expression of alphavbeta3 integrin in the endometrium of unexplained infertility patients with recurrent IVF-ET failures: improvement by danazol treatment.

PURPOSE: To determine whether there is any association between the expression of endometrial integrin alphavbeta3 and repeated IVF-ET failure and to examine the effect of danazol treatment on alphavbeta3 expression. METHODS: This prospective study was performed using a semiquantitative immunohistochemical analysis on the staining intensity of alphavbeta3 in the mid-secretory endometria derived from 10 fertile women and 57 infertile patients with a history of repeated IVF-ET failures. Nine patients randomly selected from these 22 patients with unexplained infertility were then treated with oral danazol administration for 12 weeks and reexamined at the first mid-secretory phase after the danazol treatment. RESULT(S): The levels of endometrial alphavbeta3 expression were lower in 22 patients with unexplained infertility than in the fertile control and 35 patients with explained infertility. The 9 patients treated with danazol showed a significant increase in the alphavbeta3 staining. CONCLUSION(S): The significantly decreased expression of endometrial integrin alphavbeta3 suggested that functional, but not morphological, endometrial defect may be one of the causes for the patients with unexplained infertility. Danazol may have a therapeutic potential in improving endometrial function together with up-regulation of alphavbeta3.

Danazol↗

PubMed1998

A role for the alphavbeta3 integrin in the transmigration of monocytes.

The beta2 integrins and intercellular adhesion molecule-1 (ICAM-1) are important for monocyte migration through inflammatory endothelium. Here we demonstrate that the integrin alphavbeta3 is also a key player in this process. In an in vitro transendothelial migration assay, monocytes lacking beta3 integrins revealed weak migratory ability, whereas monocytes expressing beta3 integrins engaged in stronger migration. This migration could be partially blocked by antibodies against the integrin chains alphaL, beta2, alphav, or IAP, a protein functionally associated with alphavbeta3 integrin. Transfection of beta3 integrin chain cDNA into monocytes lacking beta3 integrins resulted in expression of the alphavbeta3 integrin and conferred on these cells an enhanced ability to transmigrate through cell monolayers expressing ICAM-1. These monocytes also engaged in alphaLbeta2-dependent locomotion on recombinant ICAM-1 which was enhanced by alphavbeta3 integrin occupancy. Antibodies against IAP were able to revert this alphavbeta3 integrin-dependent cell locomotion to control levels. Finally, adhesion assays revealed that occupancy of alphavbeta3 integrin could decrease monocyte binding to ICAM-1. In conclusion, we show that alphavbeta3 integrin modulates alphaLbeta2 integrin-dependent monocyte adhesion to and migration on ICAM-1. This could represent a novel mechanism to promote monocyte motility on vascular ICAM-1 and initiate subsequent transendothelial migration.

Animals↗

PubMed2005

Interaction of human Thy-1 (CD 90) with the integrin alphavbeta3 (CD51/CD61): an important mechanism mediating melanoma cell adhesion to activated endothelium.

The expression of the alphavbeta3 integrin (CD51/CD61) on human melanoma cells has been shown to be associated most closely with tumor progression and metastases formation in melanoma. Here, we demonstrated a specific interaction of the alphavbeta3 integrin on melanoma cells with the human Thy-1, an inducible cell adhesion molecule expressed on the cell surface of activated endothelial cells (EC). The interaction was shown by the binding of purified Thy-1 protein to alpha(V)beta(3) transfected cells, to alphavbeta3-expressing melanoma cells and to purified alpha(V)beta(3) integrin. Moreover, melanoma cells adhere specifically to Thy-1 transfectants via alphavbeta3 on melanoma cells showing the functional relevance of this interaction for cell adhesion. Finally, the importance of the alphavbeta3/Thy-1 interaction for the adhesion of melanoma cells to the activated endothelium was confirmed under static and flow conditions by the inhibition of melanoma cell adhesion to and transmigration across activated EC by blocking the alphavbeta3/Thy-1 interaction. In conclusion, we have identified a new pair of adhesion molecules Thy-1 and alphavbeta3 mediating the interaction of melanoma cells and activated EC. These data explain at least in part the high tumorigenicity of alphavbeta3-expressing melanoma cells and the association of alphavbeta3-positive melanoma cells with a high risk of metastasis and poor prognosis.

Cell Adhesion↗

PubMed2001

Solid-phase synthesis of a nonpeptide RGD mimetic library: new selective alphavbeta3 integrin antagonists.

The solid-phase synthesis of a low molecular weight RGD mimetic library is described. Activities of the compounds in inhibiting the interaction of ligands, vitronectin and fibrinogen, with isolated immobilized integrins alphavbeta3 and alphaIIbbeta3 were determined in a screening assay. Highly active and selective nonpeptide alphavbeta3 integrin antagonists with regard to orally bioavailability were developed, based on the aza-glycine containing lead compound 1. An important variation is the substitution of the aspartic amide of 1 by an aromatic residue. Furthermore, different guanidine mimetics have been incorporated to improve the pharmacokinetic profile. Exchange of the beta-amino acid NH by a methylene moiety in one set of RGD mimetics leads to the azacarba analogue compounds representing a novel peptidomimetic approach, which should increase the metabolic stability.

Amidines↗

PubMed2005

Hypoxia-inducible factor regulates alphavbeta3 integrin cell surface expression.

Hypoxia-inducible factor (HIF)-deficient placentas exhibit a number of defects, including changes in cell fate adoption, lack of fetal angiogenesis, hypocellularity, and poor invasion into maternal tissue. HIF is a heterodimeric transcription factor consisting of alpha and beta aryl hydrocarbon receptor nuclear translocator or ARNT) subunits. We used undifferentiated trophoblast stem (TS) cells to characterize HIF-dependent adhesion, migration, and invasion. Arnt(-/-) and Hifalpha(-/-) TS cells exhibit reduced adhesion and migration toward vitronectin compared with wild-type cells. Furthermore, this defect is associated with decreased cell surface expression of integrin alphavbeta3 and significantly decreased expression of this integrin in focal adhesions. Because of the importance of adhesion and migration in tumor progression (in addition to placental development), we examined the affect of culturing B16F0 melanoma cells in 1.5% oxygen (O(2)). Culturing B16F0 melanoma cells at 1.5% O(2) resulted in increased alphavbeta3 integrin surface expression and increased adhesion to and migration toward vitronectin. Together, these data suggest that HIF and O(2) tension influence placental invasion and tumor migration by increasing cell surface expression of alphavbeta3 integrin.

Animals↗

PubMed1999

Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2.

Interaction between integrin alphavbeta3 and extracellular matrix is crucial for endothelial cells sprouting from capillaries and for angiogenesis. Furthermore, integrin-mediated outside-in signals co-operate with growth factor receptors to promote cell proliferation and motility. To determine a potential regulation of angiogenic inducer receptors by the integrin system, we investigated the interaction between alphavbeta3 integrin and tyrosine kinase vascular endothelial growth factor receptor-2 (VEGFR-2) in human endothelial cells. We report that tyrosine-phosphorylated VEGFR-2 co-immunoprecipitated with beta3 integrin subunit, but not with beta1 or beta5, from cells stimulated with VEGF-A165. VEGFR-2 phosphorylation and mitogenicity induced by VEGF-A165 were enhanced in cells plated on the alphavbeta3 ligand, vitronectin, compared with cells plated on the alpha5beta1 ligand, fibronectin or the alpha2beta1 ligand, collagen. BV4 anti-beta3 integrin mAb, which does not interfere with endothelial cell adhesion to vitronectin, reduced (i) the tyrosine phosphorylation of VEGFR-2; (ii) the activation of downstream transductor phosphoinositide 3-OH kinase; and (iii) biological effects triggered by VEGF-A165. These results indicate a new role for alphavbeta3 integrin in the activation of an in vitro angiogenic program in endothelial cells. Besides being the most important survival system for nascent vessels by regulating cell adhesion to matrix, alphavbeta3 integrin participates in the full activation of VEGFR-2 triggered by VEGF-A, which is an important angiogenic inducer in tumors, inflammation and tissue regeneration.

Androstadienes↗

PubMed2006

Alphavbeta3-integrin imaging: a new approach to characterise angiogenesis?

OVERVIEW: The field of angiogenesis research is one of the most rapidly growing biomedical disciplines. Great efforts are being made to develop anti-angiogenesis drugs for treatment of cancer as well as non-oncological diseases. Thus, imaging techniques allowing non-invasive monitoring of corresponding molecular processes will be of great interest. One target structure involved in the angiogenic process is the integrin alphavbeta3, which mediates the migration of activated endothelial cells during vessel formation. MATERIALS AND METHODS: A variety of radiolabelled RGD peptides have been introduced for monitoring of alphavbeta3 expression using nuclear medicine tracer techniques. OBJECTIVES: This review discusses tracer development and highlights some strategies for tracer optimisation. It summarises the preclinical and clinical data and discusses the potential of this class of tracer to characterise angiogenesis.

Animals↗