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Results for “Integrin alphaVbeta3”

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PubMed2006

Tumor-specific expression of alphavbeta3 integrin promotes spontaneous metastasis of breast cancer to bone.

INTRODUCTION: Studies in xenograft models and experimental models of metastasis have implicated several beta3 integrin-expressing cell populations, including endothelium, platelets and osteoclasts, in breast tumor progression. Since orthotopic human xenograft models of breast cancer are poorly metastatic to bone and experimental models bypass the formation of a primary tumor, however, the precise contribution of tumor-specific alphavbeta3 to the spontaneous metastasis of breast tumors from the mammary gland to bone remains unclear. METHODS: We used a syngeneic orthotopic model of spontaneous breast cancer metastasis to test whether exogenous expression of alphavbeta3 in a mammary carcinoma line (66cl4) that metastasizes to the lung, but not to bone, was sufficient to promote its spontaneous metastasis to bone from the mammary gland. The tumor burden in the spine and the lung following inoculation of alphavbeta3-expressing 66cl4 (66cl4beta3) tumor cells or control 66cl4pBabe into the mammary gland was analyzed by real-time quantitative PCR. The ability of these cells to grow and form osteolytic lesions in bone was determined by histology and tartrate-resistant acid phosphatase staining of bone sections following intratibial injection of tumor cells. The adhesive, migratory and invasive properties of 66cl4pBabe and 66cl4beta3 cells were evaluated in standard in vitro assays. RESULTS: The 66cl4beta3 tumors showed a 20-fold increase in metastatic burden in the spine compared with 66cl4pBabe. A similar trend in lung metastasis was observed. alphavbeta3 did not increase the proliferation of 66cl4 cells in vitro or in the mammary gland in vivo. Similarly, alphavbeta3 is not required for the proliferation of 66cl4 cells in bone as both 66cl4pBabe and 66cl4beta3 proliferated to the same extent when injected directly into the tibia. 66cl4beta3 tumor growth in the tibia, however, increased osteoclast recruitment and bone resorption compared with 66cl4 tumors. Moreover, alphavbeta3 increased 66cl4 tumor cell adhesion and alphavbeta3-dependent haptotactic migration towards bone matrix proteins, as well as their chemotactic response to bone-derived soluble factors in vitro. CONCLUSION: These results demonstrate for the first time that tumor-specific alphavbeta3 contributes to spontaneous metastasis of breast tumors to bone and suggest a critical role for this receptor in mediating chemotactic and haptotactic migration towards bone factors.

Animals↗

PubMed2006

RGD-dependent binding of procathepsin X to integrin alphavbeta3 mediates cell-adhesive properties.

Secreted lysosomal cysteine proteases (cathepsins) are involved in degradation and remodeling of the extracellular matrix, thus contributing to cell adhesion and migration. Among the eleven human lysosomal cysteine proteases, only procathepsin X contains an RGD motif located in a highly exposed region of the propeptide, which may allow binding of the proenzyme to RGD-recognizing integrins. Here, we have tested procathepsin X for cell-adhesive properties and found that it supports integrin alpha(v)beta(3)-dependent attachment and spreading of human umbilical vein endothelial cells. Using site-directed mutants of procathepsin X, we proved that this effect is mediated by the RGD sequence within the proregion of the protease. Endogenous procathepsin X is transported to the plasma membrane, accumulates in vesicles at lamellipodia of the human umbilical vein endothelial cell, and is partly associated with the cell surface, as shown by immunofluorescence. In addition, procathepsin X is partly co-localized with integrin beta(3), as detected by immunogold electron microscopy. A direct interaction between endogenous procathepsin X and alpha(v)beta(3) was demonstrated by co-immunoprecipitation. Moreover, surface plasmon resonance analysis revealed significant and RGD-dependent binding of procathepsin X to integrin alpha(v)beta(3). Our results provide for the first time evidence that the extracellular function of cathepsin X may include binding to integrins thereby modulating the attachment of migrating cells to ECM components.

Cathepsins↗

PubMedDate not supplied

99mTc-labeled cyclic RGDfK dimer: initial evaluation for SPECT imaging of glioma integrin alphavbeta3 expression.

This report describes the evaluation of biodistribution properties of three radiotracers, [(99m)Tc(SQ168)(EDDA)], [(99m)Tc(SQ168)(tricine)(PDA)], and [(99m)Tc(SQ168)(tricine)(TPPTS)] (SQ168 = [2-[[[5-[carboonyl]-2-pyridinyl]hydrazono]methyl]benzenesulfonic acid]-Glu(cyclo{Lys-Arg-Gly-Asp-d-Phe})-cyclo{Lys-Arg-Gly-Asp-d-Phe}; EDDA = ethylenediamine-N,N'-diacetic acid; PDA = 2,5-pyridinedicarboxylic acid; TPPTS = trisodium triphenylphosphine-3,3',3' '-trisulfonate), and their potential to image the glioma integrin alpha(v)beta(3) expression in BALB/c nude mice bearing the U87MG human glioma xenografts. It was found that all three radiotracers were able to localize in glioma tumors with a relatively high tumor uptake and long tumor retention time by binding to the integrin alpha(v)beta(3) expressed on both tumor cells and endothelial cells of tumor neovasculature. It seems that the coligand has minimal effect on integrin alpha(v)beta(3) targeting capability of the (99m)Tc-labeled RGDfK dimer, but it has a significant impact on their biodistribution properties. For example, the complex [(99m)Tc(SQ168)(tricine)(TPPTS)] has the lowest liver uptake and the highest metabolic stability in normal BALB/c nude mice. Results from SPECT imaging studies show that the glioma tumors can be clearly visualized with all three radiotracers at 4 h postinjection. Among the three radiotracers evaluated in this study, [(99m)Tc(SQ168)(tricine)(TPPTS)] has the best imaging quality and is a promising candidate for more preclinical evaluations in the future.

Animals↗

PubMed2006

Tricyclic pharmacophore-based molecules as novel integrin alphavbeta3 antagonists. Part IV: preliminary control of alphavbeta3 selectivity by meta-oriented substitution.

To establish the in vivo efficacy of alphavbeta3/alphaIIbbeta3 dual antagonists possessing a tricyclic pharmacophore, a corresponding alphavbeta3-selective antagonist was required as a control. We initially took two synthetic approaches to obtain alphavbeta3-selective antagonists based on the RGD recognition pattern or on modification of the dihedral angle between the central benzene ring and the adjacent heterocycle, but both proved unsuccessful. However, synthesis of novel antagonists with meta-substitution of the central benzene ring generated weak selectivity for alphavbeta3 over alphaIIbbeta3 for the first time in the family of compounds with the tricyclic pharmacophore. Optimization of meta-oriented antagonists furnished an alphavbeta3-selective antagonist exhibiting inhibitory activity not only in a receptor-binding assay, but also in a cell adhesion assay.

Aorta↗

PubMed2006

Multimodality imaging of tumor integrin alphavbeta3 expression.

Most solid tumors are angiogenesis dependent. Anti-angiogenic pharmaceuticals that inhibit the growth of new blood vessels offer considerable promise as anti-cancer agents. With increasing numbers of anti-angiogenic drugs in clinical trials, there is an urgent need for detailed characterization of the heterogeneity of tumor vasculature and dissection of the complex network of mechanisms that control tumor angiogenesis. Non-invasive molecular imaging will play a key role in individualized anti-angiogenic therapy based upon molecular features of the new blood vessel growth. Integrin alpha(v)beta(3), which binds several ligands via an RGD tripeptide sequence, is uniquely expressed in tumor vasculature and aggressive tumor cells, making it a potential target for anti-angiogenic interventions. This review highlights some recent advances in multimodality imaging of tumor integrin expression with emphasis on positron emission tomography (PET).

Drug Design↗

PubMed2002

Pro-angiogenic activities of CYR61 (CCN1) mediated through integrins alphavbeta3 and alpha6beta1 in human umbilical vein endothelial cells.

CYR61 (CCN1) is an extracellular matrix-associated protein of the CCN family, which also includes CTGF (CCN2), NOV (CCN3), WISP-1 (CCN4), WISP-2 (CCN5), and WISP-3 (CCN6). Purified CYR61 induces neovascularization in corneal implants, and Cyr61-null mice suffer embryonic death due to vascular defects, thus establishing that CYR61 is an important regulator of angiogenesis. Aberrant expression of Cyr61 is associated with breast cancer, wound healing, and vascular diseases such as atherosclerosis and restenosis. In culture, CYR61 functions through integrin-mediated pathways to promote cell adhesion, migration, and proliferation. Here we show that CYR61 can also promote cell survival and tubule formation in human umbilical vein endothelial cells. Furthermore, we have dissected the integrin receptor requirements of CYR61 with respect to its pro-angiogenic activities. Thus, CYR61-induced cell adhesion and tubule formation occur through interaction with integrin alpha(6)beta(1) in early passage endothelial cells in which integrins have not been activated. By contrast, in endothelial cells in which integrins are activated by phorbol ester or vascular endothelial growth factor, CYR61-promoted cell adhesion, migration, survival, growth factor-induced mitogenesis, and endothelial tubule formation are all mediated through integrin alpha(v)beta(3). These findings indicate that CYR61 is an activation-dependent ligand of integrin alpha(v)beta(3) and an activation-independent ligand of integrin alpha(6)beta(1) and that these integrins differentially mediate the pro-angiogenic activities of CYR61. These findings help to define the mechanisms by which CYR61 acts as an angiogenic regulator, provide a molecular interpretation for the loss of vascular integrity and increased apoptosis of vascular cells in Cyr61-null mice, and underscore the importance of CYR61 in the development and homeostasis of the vascular system.

Cell Adhesion↗

PubMed1999

Alphavbeta3 integrin binding affinity and specificity of SM256 in various species.

This study was undertaken to define the alphavbeta3 binding affinity and specificity of the low-molecular-weight nonpeptide integrin antagonist, SM256. SM256 demonstrated high potency (IC50, 0.057+/-0.030 nM) in inhibiting vitronectin binding to purified human alphavbeta3 receptors. Additionally, SM256 inhibited alphavbeta3-mediated human umbilical vein endothelial cell (HUVEC) or 293/beta3 (beta3-transfected cell line) adhesion to fibrinogen with IC50 values of 0.0054+/-0.0058 and 0.0023+/-0.0012 microM, respectively. SM256 demonstrated a relatively high degree of specificity for human alphavbeta3-mediated functions as compared with other human integrins including alphavbeta5 (IC50, 0.92+/-0.69 microM), alphaIIbbeta3 (IC50, 0.72+/-0.07 microM), alpha4/beta1 (IC50, >100 microM) and alpha5/beta1 (IC50, 2.3+/-2.1 microM). SM256 demonstrated different degree of species specificity in blocking alphavbeta3-mediated cellular adhesion with relatively higher affinity to dog (IC50, 0.005+/-0.002 microM), rabbit (IC50, 0.021+/-0.01 microM), mouse (IC50, 0.035+/-0.01 microM), and pig (IC50, 0.41+/-0.24 microM) endothelial or smooth-muscle cell alphavbeta3-mediated adhesion. Additionally, SM256 demonstrated high degree of alphavbeta3 specificity as compared with alphavbeta5, alpha5beta1, or alphaIIbbeta3-mediated binding in these species. SM256 is a potent alphavbeta3, antagonist with high affinity and specificity for alphavbeta3-mediated functions. Additionally, a comparable alphavbeta3 affinity for SM256 was demonstrated with endothelial cells obtained from various species (dog, mouse, rabbit, and pig) as compared with that from human.

Animals↗

PubMed2004

N-Aryl-gamma-lactams as integrin alphavbeta3 antagonists.

Novel alphavbeta3 antagonists based on the N-aryl-gamma-lactam scaffold were prepared. SAR studies led to the identification of potent antagonists for alphavbeta3 receptor with excellent selectivity against the structurally related alpha(IIb)beta3 receptor. Additional interactions of N-aryl-gamma-lactam derivatives with alphavbeta3 were found when compared to c(-RGDf[NMe]V-) peptide antagonist. The effects of the conformation and configuration of the gamma-lactam core on the binding were also assessed.

Animals↗

PubMed2003

Phenylbutyrates as potent, orally bioavailable vitronectin receptor (integrin alphavbeta3) antagonists.

In our continuing efforts to identify small molecule vitronectin receptor antagonists, we have discovered a series of phenylbutyrate derivatives, exemplified by 16, which have good potency and excellent oral bioavailability (approximately 100% in rats). This new series is derived conceptually from opening of the seven-membered ring of SB-265123.

Acetates↗

PubMed2002

Expression of alphaVbeta3 integrin in the chick embryo aortic endothelium.

The integrin chain alphaV, expressed in association with beta3, by cells of the megakaryocytic/thrombocytic and endothelial lineages is thought to play an important role in angiogenesis. alphaVbeta3 expression by endothelial cells is not constitutive but induced by various stimuli in avian and human models. Here the developmental pattern of alphaVbeta3 expression was analysed in the chick embryo by immunocytochemistry, using a specific monoclonal antibody. On day 2 of development alphaVbeta3 expression was restricted to rare cells in the blood stream, in the embryo proper and in the yolk sac blood islands. AlphaVbeta3 expression by endothelial cells became detectable on day 3 and was restricted to the dorsal aorta. Interestingly it was absent from the intra-aortic hemopoietic clusters (E3.5) which, as we have showed previously, express the alphaIIbbeta3 integrin and display progenitor potentialities. However the endothelium underlying intra-embryonic hemopoietic clusters expressed this integrin. In contrast E6-7 para-aortic hemopoietic foci contained numerous alphaVbeta3 positive cells. Both alphaVbeta3 and alphaIIbbeta3 were expressed in these latter hemopoietic sites, while alphaVbeta3 was still selectively expressed by the aortic endothelium until E6. Thereafter, at E7 the pulmonary artery also expressed it. Since alphaIIbbeta3 is expressed by avian and murine multilineage hemopoietic progenitors, we then studied the hemopoietic potentialities of alphaVbeta3/alphaIIbeta3 double positive cells from embryonic bone marrow differentiating in vitro in erythro-myeloid conditions. Thrombocytic, erythroid and myeloid progenitor potentialities were found within the cell population expressing both beta3 integrins.

Animals↗

PubMed1997

The alphavbeta3 integrin regulates alpha5beta1-mediated cell migration toward fibronectin.

This study examines the interactions of alphavbeta3 and alpha5beta1 in the regulation of cell migration. Human embryonic kidney (HEK) 293 cells that express alpha5beta1 endogenously were transfected with alphavbeta3 and beta3 mutants, and their attachment and migration to fibronectin (Fn) and vitronectin (Vn) were measured. An alphavbeta3 blocking antibody and the alphavbeta3 ligand cyclic G-Pen-GRGDSPC-A inhibited alpha5beta1-mediated migration toward Fn, but not attachment to Fn. This function was alphavbeta3-specific since alphavbeta5 transfection and alphavbeta5 blocking antibody did not produce this effect. Mutations introduced into the beta3 integrin subunit to dissect this phenomenon revealed the following. Disruption of the ligand binding domain by the Glanzmann thrombasthenia mutation beta3-D119Y constitutively abolished migration toward both Vn and Fn, and attachment to Vn but not to Fn. Insertion of the Glanzmann mutation beta3-S752P into the cytoplasmic domain or its truncation (beta3-Delta717) abolished binding to Vn but not to Fn. Inhibition of migration toward Fn was inhibited in these cells by alphavbeta3 blocking antibody. alphavbeta3-mediated inhibition was, however, abolished by truncation of the transmembrane domain (beta3-Delta693). These findings demonstrate alphavbeta3 regulation of alpha5beta1-mediated cell migration and suggest that the beta3 transmembrane domain is essential for this function.

Cell Line↗

PubMed1998

Specific interaction of the recombinant disintegrin-like domain of MDC-15 (metargidin, ADAM-15) with integrin alphavbeta3.

MDC-15 (ADAM-15, metargidin), a membrane-anchored metalloprotease/disintegrin/cysteine-rich protein, is expressed on the surface of a wide range of cells and has an RGD tripeptide in its disintegrin-like domain. MDC-15 is potentially involved in cell-cell interactions through its interaction with integrins. We expressed a recombinant MDC-15 disintegrin-like domain as a fusion protein with glutathione S-transferase (designated D-15) in bacteria and examined its binding function to integrins using mammalian cells expressing different recombinant integrins. We found that D-15 specifically interacts with alphavbeta3 but not with the other integrins tested (alpha2beta1, alpha3beta1, alpha4beta1, alpha5beta1, alpha6beta1, alpha6beta4, alphavbeta1, alphaIIbbeta3, and alphaLbeta2). Mutation of the tripeptide RGD to SGA totally blocked binding of D-15 to alphavbeta3, suggesting that D-15-alphavbeta3 interaction is RGD-dependent. When the sequence RPTRGD is mutated to NWKRGD, D-15 is recognized by both alphaIIbbeta3 and alphavbeta3, suggesting that the receptor binding specificity is mediated by the sequence flanking the RGD tripeptide, as in snake venom disintegrins. These results indicate that the disintegrin-like domain of MDC-15 functions as an adhesion molecule and may be involved n alphavbeta3-mediated cell-cell interactions.

ADAM Proteins↗

PubMedDate not supplied

Adhesion of endothelial cells to NOV is mediated by the integrins alphavbeta3 and alpha5beta1.

NOV is a member of the CCN family of matricellular proteins. We have shown previously that NOV is strongly expressed by vascular smooth muscle cells (VSMCs) of the rat carotid artery. However, 7 days after injury, NOV expression is down-regulated, except near the luminal surface of the developing intima, where it is strongly expressed. These data suggested that NOV might be involved in the regulation of endothelial cell adhesion. NOV promoted the adhesion of human umbilical vein endothelial cells (HUVECs), which was abolished by anti-NOV antibody. HUVEC adhesion to NOV required divalent cations and was inhibited by GRGDS peptide, implicating integrins in the adhesion mechanism. Monoclonal antibodies (mAbs) against alphavbeta3 inhibited adhesion of HUVECs to NOV, and NOV was shown to bind to alphavbeta3. Anti-alpha5beta1 mAbs also inhibited HUVEC adhesion to NOV, but adhesion via alpha5beta1 was mediated by fibronectin. HUVEC adhesion to NOV caused intracellular signalling, as evidenced by increased phosphotyrosine content of focal adhesion kinase. Together with evidence that NOV expression in a variety of tissues is restricted to blood vessels containing VSMCs, these data are consistent with a role for NOV in endothelial cell adhesion in vascular homeostasis and in the response to injury.

Animals↗

PubMed2001

Evidence from site-directed mutagenesis that the cytoplasmic domain of the beta3 subunit influences the conformational state of the alphaVbeta3 integrin ectodomain.

In order to explore the mechanisms leading to conformational changes of the vitronectin receptor alphavbeta3 following ligand or divalent cation binding, we have investigated the expression of epitopes known as ligand-induced binding sites (LIBS) on beta3 cytoplasmic tail mutants expressed in CHO cells. Truncation of the entire beta3 cytoplasmic domain induced constitutive LIBS exposure on alphavbeta3 and alphaIIbeta3. Deletion of the C-terminal NITY759 sequence or disruption of the NPLY747 motif by a Y747A substitution impaired extracellular conformational changes on alphavbeta3 following RGDS, echistatin or Mn2+ binding, whereas the substitutions Y747F, Y759A or Y759F allowed normal LIBS exposure. Furthermore, metabolic energy depletion totally prevented Mn2+-dependent LIBS exposure, but had only a minor effect on RGDS-induced conformational changes. Our results demonstrate that the structural integrity of the NPLY747 motif in the beta3 cytoplasmic domain, rather than potential phosphorylation of Tyr747 or Tyr759, is a prerequisite for conformational changes within the alphavbeta3 ectodomain, and suggest that two different mechanisms are responsible for RGDS- and Mn2+-dependent conformational changes.

Amino Acid Motifs↗

PubMed2000

Expression of alpha4beta1 and alphavbeta3 integrins in the endometrium of women using the T200 copper intrauterine device.

OBJECTIVE: To investigate the expression of alpha4 and beta3 integrin subunit levels in the endometrium of healthy women and copper intrauterine device (IUD) T200 users. DESIGN: Case control study. SETTING: An academic teaching hospital and a primary care clinic. PATIENT(S): Thirteen copper IUD users and 13 normal fertile women. INTERVENTION(S): Timed endometrial biopsies during the mid-secretory phase (days 20 to 24). MAIN OUTCOME MEASURE(S): Histologic dating of endometrium and immunohistochemical staining intensity of alpha4 and beta3, using the semiquantitative immunohistochemical score (HSCORE). RESULT(S): All endometrial biopsies consistent with menstrual dates were examined for integrin expression (beta3 and alpha4). No difference in alpha4 integrin expression was found between IUD users and controls in both luminal and glandular epithelium. In fertile controls, alphavbeta3 staining was present in 100% and 38.4% of glandular and luminal epithelium, respectively. In contrast, only 61.5% of the IUD users had any alphavbeta3 staining in the glandular epithelium and only 53.9% in the luminal epithelium. The intensity of immunoreactivity between the two groups (mean HSCORE) did not differ significantly. CONCLUSION(S): Proportionately, significantly fewer women using copper IUD had positive alphavbeta3 immunoreactivity in the glandular epithelium of mid-secretory endometrium.

Antibodies, Monoclonal↗

PubMed2001

Adenoviral transduction efficiency of ovarian cancer cells can be limited by loss of integrin beta3 subunit expression and increased by reconstitution of integrin alphavbeta3.

Recombinant adenoviruses expressing a therapeutic gene are currently used in clinical studies for treatment of advanced ovarian cancer. We therefore tested whether the expression level of primary (CAR) and secondary adenovirus receptors (integrins) was predictive of the efficacy of adenoviral gene transfer in ovarian cancer cells. Adenoviral transduction efficiency (ATE) was determined with an E1-deleted adenovirus type 5 expressing beta-galactosidase under a CMV promoter (AdGal). ATE was studied in relationship to the expression level of both CAR (coxsackie and adenovirus receptor) and integrins. A representative sample of 25 permanent human cell lines established from advanced ovarian cancer in our laboratory and the OV-2774 cell line were tested. Overall, ATE increased with increasing titers of AdGal. At a given titer of 50 infectious units per cell, transduction efficiency varied from 6 to 94% among the individual cell lines. All cell lines expressed CAR and integrin alpha(v)beta(5), but no relation between ATE and expression level of CAR or alpha(v)beta(5) integrin was observed. In contrast, cell lines with poor ATE, despite expressing high levels of CAR, lacked expression of integrins alpha(v)beta(3) and alpha(5)beta(1). Reconstitution of alpha(v)beta(3) integrin by reexpressing the beta(3) subunit significantly enhanced ATE of ovarian cancer cells. In ovarian cancer, neither integrins nor CAR alone appear to be potentially useful predictive markers for ATE by serotype 5 adenovirus in clinical gene therapy. A minimum level of CAR necessary for binding of adenoviruses was observed in all tested ovarian cancer cell lines. Loss of alpha(v)beta(3) integrin is frequently associated with advanced stages of ovarian cancer and can significantly reduce ATE.

Adenoviridae↗

PubMed1996

Tumor angiogenesis and the role of vascular cell integrin alphavbeta3.

Angiogenesis is a critical process for the growth and metastatic properties of all solid tumors. Recent biological and molecular studies have begun to elucidate the basic mechanisms of vascular cell proliferation, motility, and differentiation in vitro and in vivo. With this knowledge, it should be feasible to devise therapeutic strategies to selectively target and perturb the biological processes of angiogenic vascular cells, thereby leading to effective inhibitors of angiogenesis. This strategy has led to the development of antagonists to integrin alpha v beta 3, which promote the unscheduled programmed cell death of newly sprouting blood vessels. These antagonists cause regression of preestablished human tumors growing in laboratory animals and thus may lead to an effective therapeutic approach for most solid tumors in humans. Studies are currently aimed at designing highly specific small organic integrin inhibitors that will disrupt the signals enabling vascular cells to respond to the tumor-associated extracellular environment and to promote tumor-induced angiogenesis.

Adult↗

PubMed2003

Disease-associated increased HIF-1, alphavbeta3 integrin, and Flt-1 do not suffice to compensate the damage-inducing loss of blood vessels in inflammatory myopathies.

OBJECTIVE: To analyze the microvascular network in skeletal muscle biopsies from patients with dermatomyositis (DM) and systemic sclerosis (SSc) compared to polymyositis (PM) and systemic lupus erythematosus (SLE), and non-inflammatory myopathies, and to clarify whether reparative angiogenesis-related factors are expressed in parallel to blood vessel damage. METHODS: Immunohistochemical staining of muscle biopsies (10 DM, 10 SSc, 10 PM, 10 SLE, and 10 non-inflammatory myopathies) with antibodies against von Willebrand factor (vWF), hypoxia-inducible factor-1beta (HIF-1beta), beta3 integrin subunit, and vascular endothelial growth factor receptor-1 (VEGFR-1). The TechMate staining robot and biotin-streptavidin protocol were used. RESULTS: DM and SSc muscles were characterized by endothelial damage and reduction of blood vessel network. Expression of angiogenesis-related factors (HIF-1beta, beta3, VEGFR-1) was also found in the same biopsies. In contrast, in PM and SLE muscles, vascular networks were apparently not affected and angiogenic stimuli were less expressed if at all. CONCLUSIONS: This work demonstrates that in inflamed muscles hypoxia/ischemia induces increased expression of angiogenic factors, yet their impact is insufficient to repair disease-associated reduction of the capillary network. This leads to questions considering the usefulness of angiogenic factors in the treatment of ischemic inflammatory myopathies in DM and SSc.

Biomarkers↗