The role of alphav integrins during angiogenesis: insights into potential mechanisms of action and clinical development.
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Selective Sp1 and Sp3 binding is crucial for activity of the integrin alphaV promoter in cultured endothelial cells.
Human integrin alphavbeta receptors are expressed in a number of cells and their expression is regulated at the level of transcription and by post-transcriptional mechanisms. A substantial body of research exists on the structure, function, molecular biology and physiological significance of alphav integrin receptors. However, the importance of particular cis-acting DNA elements or trans-acting nuclear factors in the regulation of the alphav gene promoter is still not adequately understood. Previous functional analysis of the alphav gene 5' flanking region in transfected cultured cells identified cis elements critical for alphav transcription within a 222-bp region. To define further the location of this enhancing element, we performed DNase I footprinting of the human alphav gene promoter between -522 and the translation initiation site. For this purpose, nuclear extracts of alphavbeta3-positive cells, human umbilical vein endothelial cells, were used. Nuclear proteins of endothelial cells strongly protected essentially one region corresponding to the sequence between -194 and -172 of the alphav promoter region. Electrophoretic mobility shift assays with different oligonucleotides, and competition analysis identified a CTCCTCCTC sequence that is directly involved in the transcriptional activity of the alphav promoter. Purified Sp1 alone produced an identical footprint, and DNA binding assays using anti-Sp1 and anti-Sp3 antibodies showed that transcription factors Sp1 and Sp3 were the major nuclear proteins bound to this region.
Antigens, CD↗
Altered vitronectin receptor (alphav integrin) function in fibroblasts adhering on hydrophobic glass.
Function of integrins is crucial for adhesion, movement, proliferation, and survival of cells. In a recent study we found impaired fibronectin receptor function on hydrophobic substrata (G. Altankov et al. J Biomater Sci Polym Edn 1997;8:712-740). Here, we have studied the distribution and function of the vitronectin receptor (alphav integrin) in fibroblasts adhering on hydrophilic glass and hydrophobic octadecyl glass (ODS). The morphology of fibroblasts and the organization of actin cytoskeleton were studied and found to be altered on ODS, where the cells did not spread and possessed condensed actin. Pretreatment of the surfaces with serum or pure vitronectin improved cell morphology on both substrata, resulting in the development of longitudinal actin stress fibers. It was found with biotinylated vitronectin that comparable quantities of vitronectin were adsorbed from single vitronectin solutions or serum on glass and on hydrophobic ODS. The organization of the vitronectin receptors on the ventral cell surface was investigated in permeabilized cells showing normal focal adhesions in fibroblasts plated on glass but none of these structures on ODS. The distribution of alphav integrin on the dorsal cell surface was studied on nonpermeabilized living cells after antibody tagging. While fibroblasts adhering on plain or serum-treated glass developed a linear organization of alphav integrin, cells on plain and serum-treated ODS were not able to reorganize the vitronectin receptor. Studies on signal transduction with antiphosphotyrosine antibodies revealed co-localization of alphav integrin and phosphotyrosine in focal adhesions on glass and serum-treated glass. However, signaling was almost absent on plain ODS and weak on serum-treated ODS. It was concluded that alterations in vitronectin receptor function on the ventral cell surface caused by the hydrophobic material surface inhibit signal transfer and subsequent intracellular events that are important for the organization and function of integrins.
Actins↗
GATA-1 binding to the alphaV promoter negatively regulates expression of the integrin alphaV subunit in human leukemic K562 cells.
Recently we observed that the transcription factors Sp1 and Sp3 bind to the CTCCTCCTC sequence located between positions -194 and -172 of the alphaV promoter region and are directly involved in the regulation of transcriptional activity of the alphaV gene in human umbilical vascular endothelial cells (HUVECs) (Czyz & Cierniewski, 1999, Eur. J. Biochem. 265, 638). In this report we provide evidence that the GATA-1 factor regulates alphaV expression during differentiation of pluripotent K562 cells induced either by phorbol 12-myristate 13-acetate (PMA) or butyric acid (BA) through interaction with the GATA element in the alphaV gene promoter. DNase I footprinting analysis revealed that region -413 to -408, covering the GATA binding site, was protected by nuclear extract from K562 cells. There was no protection of this region by HUVEC nuclear extract. Electrophoretic mobility shift assay (EMSA) analysis of nuclear extract of K562 cells treated with BA revealed an increase in GATA binding activity, which was associated with reduced alphaV mRNA and alphaV protein on the cell surface. Stimulation of K562 cells with PMA resulted in opposite effects: lower expression of GATA-1 was associated with increased levels of alphaV. We conclude that the GATA-1 transcription factor specifically binds to the GATA element in the alphaV gene promoter and negatively regulates alphaV gene expression.
Amphetamine↗
Synergy between an antiangiogenic integrin alphav antagonist and an antibody-cytokine fusion protein eradicates spontaneous tumor metastases.
The suppression and eradication of primary tumors and distant metastases is a major goal of alternative treatment strategies for cancer, such as inhibition of angiogenesis and targeted immunotherapy. We report here a synergy between two novel monotherapies directed against vascular and tumor compartments, respectively, a tumor vasculature-specific antiangiogenic integrin alphav antagonist and tumor-specific antibody-interleukin 2 (IL-2) fusion proteins. Simultaneous and sequential combination of these monotherapies effectively eradicated spontaneous liver metastases in a poorly immunogenic syngeneic model of neuroblastoma. This was in contrast to controls subjected to monotherapies with either an antiangiogenic integrin alphav antagonist or antibody-IL-2 fusion proteins, which were only partially effective at the dose levels applied. Furthermore, simultaneous treatments with the integrin alphav antagonist and tumor-specific antibody-IL-2 fusion proteins induced dramatic primary tumor regressions in three syngeneic murine tumor models, i.e., melanoma, colon carcinoma, and neuroblastoma. However, each agent used as monotherapy induced only a delay in tumor growth. A mechanism for this synergism was suggested because the antitumor response was accompanied by a simultaneous 50% reduction in tumor vessel density and a 5-fold increase in inflammatory cells in the tumor microenvironment. Subsequently, tumor necrosis was demonstrated only in animals receiving the combination therapy, but not when each agent was applied as monotherapy. The results suggest that these synergistic treatment modalities may provide a novel and effective tool for future therapies of metastatic cancer.
Animals↗
Expression of coxsackie adenovirus receptor and alphav-integrin does not correlate with adenovector targeting in vivo indicating anatomical vector barriers.
Recombinant adenoviral vectors are broadly applied in gene therapy protocols. However, adenovector-mediated gene transfer has limitations in vivo. One of these is the low gene transfer rate into organs other than the liver after systemic intravenous vector injection. Local direct injection into the target organ has been used as one possible solution, but increases necessary equipment and methodology and is traumatic to the target. Wild-type adenovirus infection as well as adenovector-mediated gene transfer depends on virus interaction with the Coxsackie adenovirus receptor (CAR) mediating virus attachment to the cell surface, and on interaction with alphavbeta3 and alphavbeta5 integrins mediating virus entry into the cell. In order to assess the receptor-associated potential of different tissues to act as adenovector targets, we have therefore determined CAR and alphav-integrin expression in multiple organs from different species. In addition, we have newly determined several human, rat, pig and dog CAR-mRNA sequences. Sequence comparison and structural analyses of known and of newly determined sequences suggests a potential adenovirus binding site between amino acids 29 and 128 of the CAR. With respect to the virus receptor expression patterns we found that CAR-mRNA expression was extremely variable between different tissues, with the highest levels in the liver, whereas alphav-integrin expression was far more homogenous among different organs. Both CAR and alphav-integrin showed similar expression patterns among different species. There was no correlation, however, between the adenovector expression patterns after intravenous, intracardiac and aortic root injection, respectively, and the virus receptor patterns. In summary, many organs carry both receptors required to make them potential adenovector targets. In sharp contrast, their actual targeting clearly indicates that adenovirus receptor expression is necessary but not sufficient for vector transfer after systemic injection. The apparently very important role of anatomical barriers, in particular the endothelium, requires close attention when developing non-traumatic, organ-specific gene therapy protocols.
Adenoviridae↗
Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins.
alphav integrins have been implicated in many developmental processes and are therapeutic targets for inhibition of angiogenesis and osteoporosis. Surprisingly, ablation of the gene for the alphav integrin subunit, eliminating all five alphav integrins, although causing lethality, allows considerable development and organogenesis including, most notably, extensive vasculogenesis and angiogenesis. Eighty percent of embryos die in mid-gestation, probably because of placental defects, but all embryos develop normally to E9.5, and 20% are born alive. These liveborn alphav-null mice consistently exhibit intracerebral and intestinal hemorrhages and cleft palates. These results necessitate reevaluation of the primacy of alphav integrins in many functions including vascular development, despite reports that blockade of these integrins with antibodies or peptides prevents angiogenesis.
Animals↗
A role for alphaV integrin subunit in TGF-beta-stimulated osteoclastogenesis.
TGF-beta increases bone resorption in vivo and greatly increases osteoclast formation stimulated by receptor activator of NF-kappaB ligand (RANKL) in vitro. TGF-beta does not independently affect the differentiation state of RAW264.7 preosteoclasts, but increases cell attachment to vitronectin. This effect is mediated by increased expression of alphaV integrin subunit mRNA and protein. Concomitant with induction of osteoclast differentiation, RANKL causes relocation of alphaV to focal sites in the cell. This effect is potentiated by TGF-beta. Integrin blockade disrupts both attachment to vitronectin and RANKL-induced osteoclast formation, but culture on vitronectin has little effect. Ectopic expression of alphaV stimulates multinucleation of RAW264.7 cells and increases the number of osteoclasts formed in the presence of RANKL. These data suggest that TGF-beta potentiates RANKL-induced osteoclast formation, in part by increased expression of the alphaV integrin subunit, which may contribute to cell fusion.
Animals↗
Cloning of mouse integrin alphaV cDNA and role of the alphaV-related matrix receptors in metanephric development.
Metanephrogenesis has been a long-standing model to study cell-matrix interactions. A number of adhesion molecules, including matrix receptors (i.e., integrins), are believed to be involved in such interactions. The integrins contain alpha and beta s ubunits and are present in various tissues in different heterodimeric forms. In this study, one of the members of the integrin superfamily, alphaV, was characterized, and its relevance in murine nephrogenesis was investigated. Mouse embryonic renal cDNA libraries were prepared and screened for alphaV, and multiple clones were isolated and sequenced. The deduced amino acid sequence of the alpha-v cDNA clones and hydropathic analysis revealed that it has a typical signal sequence and extracellular, transmembrane, and cytoplasmic domains, with multiple Ca2+ binding sites. No A(U)nA mRNA instability motifs were present. Conformational analysis revealed no rigid long-range-ordered structure in murine alphaV. The alphaV was expressed in the embryonic kidney at day 13 of the gestation, with a transcript size of approximately 7 kb. Its expression increased progressively during the later gestational stages and in the neonatal period. It was distributed in the epithelial elements of developing nephrons and was absent in the uninduced mesenchyme. In mature metanephroi, the expression was relatively high in the glomeruli and blood vessels, as compared to the tubules. Various heterodimeric associations of alphaV, i.e., with beta1, beta3, beta5, and beta6, were observed in metanephric tissues. Inclusion of alphaV-antisense-oligodeoxynucleotide or -antibody in metanephric culture induced dysmorphogenesis of the kidney with reduced population of the nephrons, disorganization of the ureteric bud branches, and reduction of mRNA and protein expressions of alphaV. The expressions of integrin beta3, beta5, and beta6 were unaltered. These findings suggest that the integrin alphaV is developmentally regulated, has a distinct spatio-temporal expression, and is relevant in the mammalian organogenesis.
Amino Acid Sequence↗
Alphav integrin expression is a novel marker of poor prognosis in advanced-stage ovarian carcinoma.
PURPOSE: To analyze the possible correlation between expression of the alphav and beta1 integrin chains and survival in advanced-stage ovarian carcinomas, studying two patient groups with extremely different disease outcome. EXPERIMENTAL DESIGN: Sections from 56 primary ovarian carcinomas and metastatic lesions from 34 patients diagnosed with advanced-stage ovarian carcinoma (Fédération Internationale des Gynaecologistes et Obstetristes stages III-IV), divided into long-term (16) and short-term (18) survivors, were evaluated for expression of alphav and beta1 integrin chains using mRNA in situ hybridization. Protein expression was additionally studied in 52 specimens using immunohistochemistry. RESULTS: The mean values for disease-free survival and overall survival were 115 and 132 months for long-term survivors, as compared with 4 and 23 months for short-term survivors, respectively. Expression of alphav integrin mRNA was observed in carcinoma (18 of 56; 32%) and stromal (17 of 56; 30%) cells. beta1 integrin mRNA was similarly detected in carcinoma (25 of 56; 47%) and stromal (19 of 56; 34%) cells. No significant differences were observed when primary and metastatic lesions were compared (P > 0.05). Alphav integrin mRNA was present more often in carcinoma cells in tumors of short-term survivors (P = 0.017 for carcinoma cells). In univariate survival analysis for all cases, alphav integrin mRNA expression in tumor cells correlated with poor survival (P = 0.012). This finding retained its predictive power in a multivariate survival analysis, in which all of the molecules studied previously in this patient cohort were included (P = 0.031). Immunohistochemistry confirmed the differences in alphav integrin expression in tumor cells of short-term as compared with long-term survivors, whereas beta1 integrin protein expression was comparable in the two groups. CONCLUSIONS: To our best knowledge, this is the first evidence associating integrin expression with poor survival in ovarian carcinoma. Alphav integrin is, thus, a novel prognostic marker in advanced-stage ovarian carcinoma.
Adult↗
Mouse integrin alphav promoter is regulated by transcriptional factors Ets and Sp1 in melanoma cells.
A 17-bp region between the -31 and -15 bp region of the mouse integrin alphav gene is known to be one of the cis-acting elements for promoter activity. Experimental binding of nuclear proteins to the -31/-15 region reveals that the -27/-16 region mediates the binding. The -27/-16 region, GGCTCCTCCTCC, has a TCCTCC motif, one of the Sp1 binding motifs. An anti-Sp1 IgG and an Sp1-binding oligonucleotide interfered with the binding of nuclear proteins to the -27/-16 oligonucleotide, demonstrating that Sp1 binds to the -27/-16 region. In addition to the -27/-16 region, two other regions, -108/-89 and -64/-44, were found to bind to nuclear proteins within the -108/+1 alphav promoter region. An oligonucleotide containing the Ets-binding consensus sequence of CAGGAAGT interfered with their binding, indicating that both regions have a functional Ets-binding site; which is ACGGAAGT from -106 to -99 bp and ACTTCCTC from -61 to -54 bp, as deduced from the sequence. Mutations in or deletions from any one of three cis-acting elements, the two Ets-binding sites or one Sp1-binding site, remarkably decreased the promoter activity detected in the -108/+1 region. Cotransfection of both Sp1 and Ets-1 cDNAs with the -108/+1 region into B16F10 cells increased the promoter activity 2.9-fold. These results demonstrate that Sp1 and Ets cooperate to activate the -108/+1-alphav promoter region.
Animals↗
Expression of alphav integrin family in gastric carcinomas: increased alphavbeta6 is associated with lymph node metastasis.
To investigate the alterations as to integrin expression in human gastric carcinomas, we analyzed the alphav subunit and 5 types of beta subunits using reverse transcription-polymerase chain reaction (RT-PCR) and competitive RT-PCR. The incidence of alphav, beta6 and beta8 expression was significantly higher in carcinoma tissues than in non-neoplastic gastric mucosal tissues (NGMTs). Out of 18 carcinoma cases with coexpression of alphav and beta6 subunits, which was demonstrated by RT-PCR, 17 cases (94%) showed lymph node metastasis (p = 0.0033). This tendency was confirmed by immunohistochemistry; most cases (23/28, 82%) in which alphavbeta6 integrin was immunohistochemically detected showed lymph node metastasis (p = 0.0193). RT-PCR and immunohistochemical studies showed that gastric carcinoma tissues expressed beta5 subunit in all cases. Furthermore, in a quantitative analysis using competitive RT-PCR, the mean level of beta5 expression was approximately 140 times higher in gastric carcinomas than in NGMTs. Most gastric carcinoma cases (27/38, 71%) were immunohistochemically positive for beta8 subunit. These findings suggest that some members of the alphav integrin family (alphavbeta5, alphavbeta6, alphavbeta8) are up-regulated, and that alphavbeta6 integrin may be involved in the lymphatic metastasis of gastric carcinomas.
Aged↗
In vivo therapy of malignant melanoma by means of antagonists of alphav integrins.
Integrin alphavbeta3 (vitronectin receptor) has been implicated in human malignant melanoma progression and angiogenesis as a receptor that provides survival signals. However, little is known about the therapeutic potential of antagonists of alphavbeta3. In this report, we characterize the activities of 2 antagonists of alphavbeta3 integrins: a human specific monoclonal antibody (MAb), 17E6, and a cyclic RGD peptide that blocked cell adhesion and induced detachment of previously substrate-attached cells in vitro. In vivo, alphavbeta3 antagonists behaved as anti-tumor drugs in a dose- and time-dependent manner. Moreover, different therapeutic treatments proved to be effective even in the therapy of established macroscopic tumor masses, thus supporting the use of these antagonists in clinical therapy. Using a panel of 6 human melanomas and 5 carcinomas, MAb 17E6 efficiently blocked the in vivo tumor growth of melanomas expressing alphavbeta3 as xenografts but did not affect the alphavbeta3-negative (although alphav integrin-positive) tumors. This demonstrated that alphavbeta3 is a pivotal integrin for the growth of human melanomas. Furthermore, since MAb 17E6 does not recognize murine alphavbeta3, the effect is due only to the direct anti-tumor activity and not to the well-known anti-angiogenic activity of alphav-integrin antagonists. Taken together, our results confirm the essential role of alphavbeta3 integrin in the growth of human malignant melanoma in vivo and provide strong evidence of the therapeutic potential of alphav-integrin antagonists for the treatment of such tumors.
Animals↗
alphaV Integrins on HT-29 colon carcinoma cells: adhesion to fibronectin is mediated solely by small amounts of alphaVbeta6, and alphaVbeta5 is codistributed with actin fibers.
HT-29 colon carcinoma cells form liver metastases upon intrasplenic injection, and adhesion to fibronectin under the liver microvascular liver endothelium is likely to be important for metastasis formation. We have therefore studied the integrins involved in fibronectin adhesion. This was not affected by blocking antibodies against the beta1, alpha3, and alpha5 integrin subunits, but it was blocked by an RGD-containing peptide, indicating involvement of RGD-dependent non-beta1 alphaV integrins. Both alphaVbeta5 and alphaVbeta6 were detected on HT-29 cells. Blocking mAb against alphaV, but not against alphaVbeta5, abolished adhesion. From a HT-29 cell lysate, only alphaVbeta6 bound to a fibronectin-Sepharose column. Thus, alphaVbeta6 is the main fibronectin receptor on HT-29 cells, despite the very low levels of alphaVbeta6 and the much higher levels of alphaVbeta5. The HT29 cells did not spread on fibronectin in the absence of serum, not even after a three- to fourfold increase in alphaVbeta6 levels, induced by interleukin 4. The cells did spread on vitronectin. Using immunofluorescence we observed that both on vitronectin and on fibronectin alphaVbeta5 was arranged in a striped pattern, aligned with actin fibers, and not in focal adhesions. On fibronectin, but not on vitronectin, alphaVbeta6 was concentrated in a punctate pattern at the periphery of cell islands.
Actins↗
Altered adhesion properties and alphav integrin expression in a cisplatin-resistant human ovarian carcinoma cell line.
In order to elucidate the mechanisms underlying the development of chemoresistance in ovarian cancer, we have previously established the IGROV1-R10 cisplatin-resistant cell line by mimicking a clinical protocol of drug administration on IGROV1 human ovarian carcinoma cells. Both IGROV1 and IGROV1-R10 cells were able to grow as a monolayer and to release cell clusters into the medium. However, IGROV1-R10 cells exhibited an enhanced capacity to detach from the monolayer as compared to the parental cells. When substrate adhesion was prevented, IGROV1-R10 cells were able to survive and to proliferate as cell clusters, even at a low cell density, whereas IGROV1 cells massively died. To explore the underlying mechanisms, we have been interested in alphav integrins, which have been implicated in some aspects of ovarian cancer biology. Both IGROV1 and IGROV1-R10 adherent cells expressed alphavbeta3 integrin. During cell growth, alphavbeta5 integrin accumulated at the surface of a majority of IGROV1-R10 cells from the monolayer, whereas only a faint expression of this integrin was observed in a minority of IGROV1 cells. The growth of IGROV1-R10 cells, but not of IGROV1 cells, was partly inhibited by a specific alphavbeta5-blocking antibody suggesting that alphavbeta5 integrin contributed to IGROV1-R10 cell proliferation.
Adenocarcinoma↗
Expression of alphav integrins and vitronectin receptor identity in breast cancer cells.
In the present study we have used fluorocytometry and immunoprecipitation to characterize the expression of alphav-containing integrins in a panel of eight human breast cancer cell lines and one normal human mammary epithelial line. We show that the classical vitronectin receptor alphavbeta3 is expressed in only one cell line (MDA-MB-231), whereas alphavbeta5 is expressed on all breast cancer cell lines and alphavbeta1 is expressed on the majority. Using adherence assays to purified ligands in the presence and absence of function-blocking monoclonal antibodies, we have demonstrated that alphavbeta5 mediates adhesion to vitronectin in the majority of these cells. In one cell line, ZR75-1, alphavbeta1 contributes significantly to adhesion to immobilized vitronectin. The formation of focal adhesions containing the alphav and beta1 subunits on vitronectin is also demonstrated by indirect immunofluorescence.
Breast Neoplasms↗
The regulation of proliferation and differentiation in oligodendrocyte progenitor cells by alphaV integrins.
We have previously shown that oligodendrocyte progenitor cells exhibit developmental switching between alphav-associated beta integrin subunits to sequentially express alphavbeta1, alphavbeta3 and alphavbeta5 integrins during differentiation in vitro. To understand the role that alphavveta3 integrin may play in regulating oligodendrocyte progenitor cell behaviour, cells of the rat cell line, CG-4, were genetically engineered to constitutively express alphavbeta3 integrin by transfection with full-length human beta3 integrin subunit cDNA. Time-lapse videomicroscopy showed no effect of beta3 expression on cell migration but revealed enhanced proliferation on vitronectin substrata. Comparison of mitotic indices, as measured by 5-bromo-2'-deoxyuridine incorporation, confirmed that human beta3 integrin-expressing cells exhibited enhanced proliferation, as compared to both vector-only transfected, and wild-type CG-4 cells when switched to differentiation medium from growth medium, but only in cultures grown on vitronectin and not on poly-D-lysine. The effects on proliferation were inhibited by a function-blocking antibody specifically directed against the human beta3 integrin subunit. Human beta3 integrin-expressing cells also exhibited reduced differentiation. This differentiation could be reduced still further by a function-blocking monoclonal antibody against alphavbeta5 integrin, as could differentiation in the wild-type CG-4 cells. Taken together, these results suggest that alphavbeta3 integrin may regulate oligodendroglial cell proliferation and that both downregulation of alphavbeta3 integrin expression and signalling through alphavbeta5 integrin may be critical to continued differentiation in vitro.
Animals↗
The effects of estrogen, its antagonist ICI 182, 780, and interferon-tau on the expression of estrogen receptors and integrin alphaV beta 3 on cycle day 16 in bovine endometrium.
We have shown previously that downregulation of intercaruncular stromal integrin alphavbeta3 in bovine endometrium on day 16 of the estrous cycle coincided with the antibody recognition of estrogen receptors (ER) in the luminal epithelium. In pregnancy, these changes were not observed. Our hypothesis was that on day 16 of the estrous cycle, estrogen from the dominant follicle causes a reduction in integrin alphavbeta3 and affects ERalpha in the luminal epithelium. The pregnancy recognition protein, interferon-tau (IFN-tau), may prevent downregulation of integrin alphavbeta3 and suppress ERalpha expression in the luminal epithelium. On days 14 to 16, heifers received uterine infusions of the anti-estrogen ICI 182, 780, estradiol 17beta, IFN-tau or the saline control. On day 16, reproductive tracts were collected for analysis of integrin alphavbeta3 and ERalpha. Estrogen receptor alpha immunoreactivity was largely restricted to the luminal epithelium in control animals. Using anti-ERalpha recognizing the amino terminus, estrogen-treated animals showed reactivity in the stroma, shallow and deep glands and myometrium as is typical of estrus, whereas ICI 182, 870 treated heifers showed little or no reactivity. In contrast, carboxyl terminus-directed antibodies showed a widespread distribution of ERalpha with reactivity detected in the uterine epithelium, stroma and myometrium of both estrogen and ICI 182, 780 treated animals. Heifers treated with IFN-tau had low ERalpha reactivity overall. Control and IFN-tau treated heifers had lower intercaruncular stromal expression of integrin alphavbeta3 in comparison to estrogen and ICI 182, 780 treatments. Overall, the results suggest that on day 16 of the estrous cycle, estrogen effects on integrin alphavbeta3 are indirect and do not directly involve ERalpha in the luminal epithelium. During pregnancy, interferon-tau may block ERalpha in the luminal epithelium but likely does not rescue integrin alphavbeta3 expression.
Animals↗