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PubMed1990

Experimentally induced murine rhabdomyosarcomas--correlation between cellular contacts, matrix formation and cellular differentiation.

Rhabdomyosarcomas (RMSs) consist of a mixture of primitive mesenchymal cells as well as cells showing various stages of rhabdomyomatous differentiation. The qualitative and quantitative degree of the rhabdomyomatous differentiation of the cells, evaluated by their morphology and expression of defined structural and functional proteins, is accepted as the basis of diagnosis and is considered to be related to the biological behaviour of RMSs. Therefore we investigated solid experimentally induced murine RMSs, adherent (subconfluent, confluent) cell cultures obtained therefrom, and also suspension cultures and studied the expression of muscular differentiation markers (vimentin, desmin, myoglobin) and the formation of extracellular matrix components (fibronectin, laminin). When we compared solid tumours with adherent cell cultures of decreasing cell densities (confluent up to single cells) and with cells grown in suspension, we found a gradual decline of differentiation ("dedifferentiation"). This decline paralleled the decrease of cell-cell and cell-substrate contacts. In suspension cultures, cells were prevented from interacting with each other and the substratum, no rhabdomyomatous differentiation of the cells took place. If restoration of cellular contacts was allowed, either by adherent growth or by reinoculation into nude mice, the process of dedifferentiation was completely reversible. Consequently, it was demonstrated that the increase of cell-cell and cell-substrate contacts was strongly associated with the appearance or increasing expression of the desmin intermediate filament cytoskeleton and with formation of the extracellular matrix components fibronectin and laminin. The microfilament (F-actin) system was modulated from an impressive stress-fiber system in subconfluent to a dense network in confluent monolayers. The extent of cell-substrate contacts, mediated by extracellular matrix components, and the number of cell-cell interactions are responsible for the capability of a malignant mesenchymal cell, which is able to undergo rhabdomyomatous differentiation, to achieve the various stages of maturation.

Animals↗
PubMed2006

Plasma matrix metalloproteinase-9 level is correlated with left ventricular volumes and ejection fraction in patients with heart failure.

BACKGROUND: Matrix metalloproteinases (MMPs) can alter myocardial extracellular matrix and thereby contribute to adverse ventricular remodeling in progressive heart failure (HF). We hypothesized that increased plasma MMP levels correlate with increased left ventricular (LV) volumes and reduced LV ejection fraction (LVEF) in patients with HF. METHODS AND RESULTS: In the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) trial, patients with symptomatic HF and LVEF <0.40 were randomized to receive various combinations of therapies with candesartan, enalapril, and metoprolol CR. Left ventricular end-diastolic volume (EDV), end-systolic volume (ESV), and LVEF were determined by radionuclide angiography at baseline and at Week 43. Baseline and Week 43 plasma MMP-2, MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) were measured by enzyme-linked immunosorbent assay in 184 patients in this substudy. At baseline, plasma MMP-9 correlated positively with ESV (Spearman's rank correlation coefficient rho = 0.17, P = .02) and negatively with LVEF (rho = -0.18, P = .01). After 43 weeks, LVEF, EDV, and ESV increased significantly (all P < .01); MMP-2 level increased (P = .01), but MMP-9 and TIMP-1 levels did not change significantly overall in the study population. Temporal changes in MMP-9 level were inversely correlated with changes in LVEF (rho = -0.16, P = .04). In multivariable analysis adjusting for clinical characteristics and treatment, a smaller proportional change in MMP-9 level after 43 weeks (below versus above median) predicted a concurrent improvement in LVEF (odds ratio = 2.35, 95% CI 1.24-4.46; P < .01). Similar relationships for MMP-2 and TIMP-1 were not observed. CONCLUSIONS: Elevated plasma MMP-9 levels correlated with lower LVEF and higher ESV, whereas increasing MMP-9 levels are associated with a concurrent deterioration of LV function. These findings suggest that monitoring of plasma markers of myocardial matrix remodeling may provide important prognostic information with respect to ongoing adverse LV remodeling in HF patients.

Aged↗
PubMed2001

Estimating spatio-temporal receptive fields of auditory and visual neurons from their responses to natural stimuli.

We present a generalized reverse correlation technique that can be used to estimate the spatio-temporal receptive fields (STRFs) of sensory neurons from their responses to arbitrary stimuli such as auditory vocalizations or natural visual scenes. The general solution for STRF estimation requires normalization of the stimulus-response cross-correlation by the stimulus autocorrelation matrix. When the second-order stimulus statistics are stationary, normalization involves only the diagonal elements of the Fourier-transformed auto-correlation matrix (the power spectrum). In the non-stationary case normalization requires the entire auto-correlation matrix. We present modelling studies that demonstrate the feasibility and accuracy of this method as well as neurophysiological data comparing STRFs estimated using natural versus synthetic stimulus ensembles. For both auditory and visual neurons, STRFs obtained with these different stimuli are similar, but exhibit systematic differences that may be functionally significant. This method should be useful for determining what aspects of natural signals are represented by sensory neurons and may reveal novel response properties of these neurons.

Acoustic Stimulation↗
PubMed1990

Constructing an instrument to measure the rate of aging in female pigtailed macaques (Macaca nemestrina).

To develop a battery of innocuous tests measuring individual differences in the rate of biological aging, longitudinal data were gathered on 28 biochemical, physiological, and morphological characteristics of 40 adult female pigtailed macaques. The change in each variable over time, i.e., the beta coefficient of linear regression, was calculated for each animal, and a matrix of correlations among the variables was constructed. Eight variables correlated well with the first principal component of the matrix. These variables (rate of fingernail growth, blood lymphocytes, mean corpuscular hemoglobin, immunoglobulin A, and serum sodium, chloride, total protein, and creatinine) represented the best subset of the potential biomarkers analyzed to produce an index covering a range of morphologic and functional systems that change with age. A similar set representing a wider range of systems and measured over a larger fraction of the life span should provide a valid index of an individual's rate of biological aging.

Aging↗
PubMed2005

[Expressions of CD147 and matrix metalloproteinase-2 in breast cancer and their correlations to prognosis].

BACKGROUND & OBJECTIVE: Matrix metalloproteinases (MMPs) play an important role in invasion and metastasis of cancers. CD147, an inducer of MMPs, can activate the expression of multiple MMPs in cancer cells and interstitial cells. This study was to investigate the correlations of CD147 and MMP-2 expressions in tumor and adjacent tissue to metastasis, invasion, and prognosis of breast cancer. METHODS: Expressions of CD147 and MMP-2 in 112 specimens of breast cancer and adjacent tissue were detected by EnVision immunohistochemistry. RESULTS: Positive rate of CD147 was 49.1% in breast cancer tissues, and 0 in adjacent tissues and interstitial cells. Positive rate of MMP-2 was 33.1% in breast cancer tissues, and 53.6% in normal adjacent tissues. The intensity of MMP-2 staining in normal tissue was positively related with tumor size, lymph node metastasis, and clinical stage (P < 0.01). CD147 staining in cancer tissue was positively related with lymph node metastasis, estrogen receptor(ER) expression, and pathologic grade (P < 0.01). Univariate analysis indicated that the overall survival rate was significantly lower in patients with positive expression of CD147 or MMP-2 than in patients with negative expression (P < 0.05). Multivariate analysis showed that CD147 was a risk predictor; the higher expression of CD147, the shorter survival time of the patients. CONCLUSIONS: MMP-2 and its inducer CD147 maybe participate in invasion and metastasis of breast cancer. CD147 may be an independent prognostic factor and, when used in combination with pathologic grading and clinical staging, may increase accuracy of predicting prognosis of patients with breast cancer.

Adult↗
PubMed2001

Expression of matrix metalloproteinases and their inhibitors correlates with invasion and metastasis in squamous cell carcinoma of the head and neck.

BACKGROUND: Matrix metalloproteinases (MMPs) have been implicated in the invasion and metastasis of head and neck squamous cell carcinoma (HNSCC). However, a detailed analysis of MMPs and tissue inhibitors of MMPs (TIMPs) in relation to the biological behavior of HNSCC has yet to be performed in clinical material. OBJECTIVES: To study a comprehensive profile of MMPs and their 2 main inhibitors in HNSCC tissue samples and to correlate the patterns of expression with clinicopathological characteristics, invasion, and metastasis. DESIGN: This study included 54 consecutive patients with primary HNSCC, 27 of which showed lymph node metastasis. Expression of MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, MMP-11, MMP-13, MMP-14, TIMP-1, and TIMP-2 was simultaneously analyzed in tissue homogenates using semiquantitative reverse transcription-polymerase chain reaction assay. Where feasible, levels of protein and enzyme activity were confirmed by Western blot, enzyme-linked immunosorbent assay, and substrate zymography. Conventional clinicopathological features, including mode of tumor invasion, were also examined. RESULTS: Significantly higher MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, MMP-11, MMP-13, and TIMP-1 levels were found in tumors vs specimens of matched normal mucosa. No difference in the distribution of MMPs and TIMPs in relation to age, sex, tumor site, or histological grade was observed. A significant correlation was demonstrated between levels of MMP-1, MMP-9, and TIMP-1 and advanced T stage and between MMP-9 expression and an infiltrative pattern of growth. Enhanced expression of MMP-9 was strongly correlated (P<.001) and levels of MMP-2, MMP-7, and MMP-11 were weakly correlated (P =.03-.05) with lymph node involvement. CONCLUSIONS: Overexpression of multiple MMPs and TIMPs is characteristic of HNSCC, and analysis of specific MMPs, MMP-9 in particular, might be useful for evaluating the malignant potential in individual HNSCC.

Adult↗
PubMed2000

The effect of egg albumin on the crystalline properties of carbamazepine in sustained release hydrophilic matrix tablets and in aqueous solutions.

The influence of egg albumin (EA) on the crystal habit properties of carbamazepine (CBZ) in aqueous solutions, solid-state, and in sustained release matrix tablets was investigated using differential scanning calorimetry (DSC), hot-stage microscopy (HSM), X-ray powder diffraction (XRD), scanning electron microscopy (SEM) and contact angle goniometer (CAG). The results suggest that in solid-state mixtures, EA affected the polymorphic transitions of CBZ from the beta to the alpha form. In hydrated matrix tablets and aqueous solutions, EA influenced the conversion rate of CBZ to the dihydrate form depending on EA concentration. It was found that increasing EA concentration enhanced CBZ dihydrate aggregation, an effect that leads to the formation of crystals with high mechanical strength and decrease of CBZ solubility. Possible mechanisms, which explain crystal growth and aggregation, as well as alteration of CBZ polymorphic transitions in the solid-state, gel layer, and in aqueous solution were suggested. In the gel layer of hydrated tablets the kinetics of CBZ transformation to the dihydrate form, crystal growth and aggregation were influenced by various processes: matrix hydration, erosion mechanism and the formation of metastable conditions, which favor aggregation and growth. The release kinetics of CBZ from the matrix highly correlated with the crystalline and morphological changes occurring in the matrix.

Anticonvulsants↗
PubMed2004

Human cortical fibroblast responses to high glucose and hypoxia.

BACKGROUND/AIMS: Approximately 30% of individuals with diabetes mellitus are susceptible to diabetic nephropathy, whereas ischemic injury uniformly induces renal impairment. As matrix accumulation correlates with progressive renal disease we assessed parameters associated with matrix turnover in response to high glucose +/- hypoxia in human cortical fibroblasts (CF). METHODS: CF were grown to confluence and exposed to media containing 5 or 25 mmol/l D-glucose for 72 h with or without a superimposed hypoxic insult. RESULTS: High glucose increased cellular protein content (p < 0.05). Combined high glucose and hypoxia induced a further increase in cellular protein content (p < 0.005), suggestive of a synergistic hypertrophic effect. MMP secretion corresponded inversely with changes in TIMP expression. In cell cultures derived from 2/3 of patients, high glucose increased MMP-9 (p < 0.0005) and MMP-2 (p < 0.005) while TIMP-1 was reduced (p = 0.05). In the remaining cell cultures derived from 1/3 of patients, MMP-2 was reduced (p < 0.0001) while TIMP-1 and TIMP-2 were both increased (p < 0.05). In contrast, hypoxia induced uniform reductions in MMP-9 and MMP-2 in both normal and high glucose conditions. High glucose increased the expression of PAI-1 mRNA (p < 0.05) in all patients independent of changes in the MMP-TIMP axis. CONCLUSIONS: In summary, variability was observed in the MMP-TIMP axis following exposure to high glucose. In contrast, high glucose uniformly induces PAI-1 expression. Hypoxic insults uniformly reduce matrix breakdown independent of the prevailing glucose conditions.

Cell Count↗
PubMed2006

Matrix metalloproteinase-9 activity in plasma correlates with plasma and whole blood lead concentrations.

Matrix metalloproteinases (MMPs) are enzymes involved in the degradation of the extracellular matrix. MMP-2 and MMP-9 have been implicated in a variety of pathological conditions including cardiovascular and neoplastic diseases, and recent studies have shown that circulating concentrations of MMP-9 may be a marker helping in the diagnosis and prognosis of cardiovascular and neoplastic diseases. We investigated whether there is an association between plasma MMP-2 and MMP-9 activities and the concentrations of lead in whole blood (blood Pb) or plasma (plasma Pb) from 40 lead-exposed persons (22 men and 18 women). Plasma Pb was determined by inductively coupled plasma mass spectrometry (ICP-MS) and blood Pb by graphite furnace atomic absorption spectrometry (GF-AAS). Plasma MMP-2 and MMP-9 activities were measured by gelatin zymography. We found a significant correlation between pro-MMP-9 activity in plasma and blood Pb (r=0.454; P=0.003), and between pro-MMP-9 activity in plasma and plasma Pb (r=0.312; P=0.049). No significant correlations were found between blood Pb or plasma Pb and plasma MMP-2. The association between pro-MMP-9 activity in plasma and both blood Pb and plasma Pb concentrations suggests a mechanism through which low lead exposure may increase the susceptibility to cardiovascular and neoplastic diseases. A causal relationship, however, remains to be proved.

Adolescent↗
PubMed2001

Transmyocardial laser revascularization induced angiogenesis correlated with the expression of matrix metalloproteinases and platelet-derived endothelial cell growth factor.

OBJECTIVE: Transmyocardial laser revascularization (TMLR) has been widely evaluated as a treatment for ischemic myocardium. However, its mechanism remains unclear. One mechanism is angiogenesis. This study examines the relationship between TMLR and angiogenesis from the viewpoint of matrix metalloproteinases and platelet-derived endothelial cell growth factor. METHODS: The left anterior descending coronary artery (LAD) was ligated permanently in 12 beagle dogs. TMLR was accomplished in six of the 12 dogs using a carbon dioxide laser. No laser treatment was done in the six control dogs. Two weeks after the initial operation, dogs were euthanized and transmural samples (each of approximately 0.5 g) were cut from the center of the infarcted LAD territory, right ventricular wall, left circumflex artery perfuse area and interventricular septum except the LAD perfuse area. They were snap-frozen in liquid nitrogen for matrix metalloproteinases and platelet-derived endothelial cell growth factor activity analysis. Hematoxylin and eosin staining, double immunohistologic staining with anti-proliferating cell nuclear antigen and von Willebrand factor antibody, and immunohistologic staining with antibody against platelet-derived endothelial cell growth factor were performed for histologic studies. The activities of matrix metalloproteinases were examined by gelatin zymography. The activity of platelet-derived endothelial cell growth factor was examined by a spectrophotometric method. RESULTS: The channels were found to be infiltrated with granulation tissue and fibrosis. In the laser group, the active matrix metalloproteinase-2 and platelet-derived endothelial cell growth factor activity in the area of the left anterior descending coronary artery was significantly higher than in the control group (P<0.0001 and P=0.037, respectively). Within the channel remnants or close to these areas, the number of von Willebrand factor positive microvessels and proliferating cell nuclear antigen with correlating von Willebrand factor positive microvessels were significantly higher than in the control group (P=0.001 and P=0.0006, respectively). These increases in microvessels significantly correlated with the expression of matrix metalloproteinases and platelet-derived endothelial cell growth factor. CONCLUSION: Based on these findings it was concluded that transmyocardial laser revascularization induced angiogenesis correlated with the expression of active matrix metalloproteinases-2 and platelet-derived endothelial cell growth factor.

Animals↗
PubMed2002

Local approximation of the correlation energy functional in the density matrix functional theory.

A local approximation formula of the correlation energy functional E(c) in terms of the first-order reduced density matrix (1-RDM) is presented. With the contracted Schrödinger equation the principal dependence of E(c) on the natural occupation numbers n(i) is identified. Using the effective mass theory, E(c) is expressed as a functional of the local density and the local variable, J = SUM (i)[square root of (n(i)(1-n(i))] /phi(i)/(2), where phi(i) are the natural spin orbitals. This local approximation satisfies the homogeneous coordinate scaling relation, gives the exact result for a one-electron system, and is almost free from the exchange energy error. It reproduced about 90% of the correlation energies of atoms and molecules.

Journal Article↗
PubMed2003

Can intrasac pressure monitoring reliably predict failure of endovascular aneurysm repair?

PURPOSE: To determine if pressure measured at a single location within aneurysm sac thrombus accurately reflects the force applied to the aneurysm wall and the risk of rupture by examining (1) if pressure is distributed uniformly within aneurysm thrombus, (2) the pressure transmission through aneurysm thrombus, and (3) the microstructural basis for pressure transmission. METHODS: Pressure within aneurysm thrombus was measured by direct puncture through the aneurysm wall at 121 sites in 26 patients during open abdominal aortic aneurysm repair. Measurements were taken prior to cross clamping and compared with intrasac pressure measured at 30 sites in 6 patients without aneurysm thrombus (controls). Transmission of pressure through aneurysm thrombus was further examined ex vivo by subjecting fresh thrombus to a pressure gradient in a custom-made pressure cell. Pressure transmission was correlated with matrix density as determined by light microscopy and image analysis. RESULTS: Mean pressure within aneurysm thrombus was higher than mean systemic pressure in 11 patients, lower in 1, and identical in 9. In 5 patients, the pressure was greater than systemic in some areas of the thrombus but less in others. Sac pressure was identical to systemic pressure at all sites in the controls. In 12 thrombus specimens (6 patients) examined in the pressure cell, pressure transmission varied significantly between specimens, correlating directly with matrix density (R(2)=0.747, p=0.001). CONCLUSIONS: Pressure transmission through aneurysm thrombus is variable and depends upon the microstructure of the thrombus. Pressure measured at a single location may not, therefore, accurately reflect the pressure acting on the aneurysm wall.

Angioplasty↗
PubMed2001

Matrix metalloproteinase-1 promoter polymorphism 1G/2G is correlated with colorectal cancer invasiveness.

PURPOSE: Matrix metalloproteinase-1 (MMP-1) is likely to be involved in invasion and metastasis of several tumors by degrading the extracellular matrix. A single guanine insertion polymorphism (2G) in the MMP-1 promoter region creates an Ets binding site causing the elevation of transcriptional level and local expression of MMP-1. The aim of this study was to evaluate the impact of this 2G insertion type polymorphism on invasion and metastasis of colorectal cancer (CRC). EXPERIMENTAL DESIGN: We genotyped for this 1G/2G polymorphism 60 patients, who were operated on for CRC and followed for 6-30 months (median: 21). A control population of 164 age- and sex-matched tumor-free subjects was also genotyped for the same polymorphism. RESULTS: The proportion of 2G homozygotes was higher in the CRC group than in the controls (P = 0.014; odds ratio, 2.21; 95% confidence interval, 1.17-4.16). The CRC group was divided in a group without metastasis (M-) and a group that had developed metastasis (M+). At the time of diagnosis, 2G homozygotes were more represented in the M+ group than in M- (P = 0.0082; odds ratio, 4.73; 95% confidence interval, 1.46-15.26). The difference between M- patients and controls did not achieve statistical significance (P = 0.52). CONCLUSIONS: Our results suggest that the presence of 2G polymorphism at the MMP-1 promoter region may favor the growth and the metastatic process in CRC patients and could be looked at as a risk factor for a worse prognosis.

Adult↗
PubMed1978

Amino acid transport in human ciliary epithelium.

A statistical study of the co-variation of the concentrations of 19 amino acids and related compounds from 21 persons was performed as a factor analysis of Caq/Cpl and of Caq. Six factors explained about 83% of the observed variation. Factor 1 showed a correlation to alpha-amino-N-butyric acid, valine, methionine, isoleucine, leucine, tyrosine and phenylalanine, factor 2 to lysine, histidine, arginine and glutamine (containing serine), factor 3 to taurine and proline, factor 4 to glycine and cystine, factor 5 to urea and factor 6 to glutamic acid. Only alanine and threonine showed a correlation to different factors in the Caq/Cpl- and the Caq-matrix. This correlation of groups of substances to different and independent factors is considered to be an argument in favour of the existence of six transport systems in the ciliary epithelium for the investigated substances.

Amino Acids↗
PubMed2003

[Controlled expression of matrix metalloproteinase 9 promotes expression of invasive phenotype of human melanoma cells].

OBJECTIVE: To investigate the correlation between matrix metalloproteinase 9 (MMP-9) expression and tumor metastasis, and explore the potential application of controlled expression of target gene in tumor gene therapy. METHODS: One self-contained tetracycline-regulated retroviral vector containing sense cDNA of MMP-9 was constructed and transfected into an early-stage human melanoma cell line WM35, which did not express MMP-9. In vitro tests such as growth rate, MTT method, 3H-thymidine incorporation, colony forming ability in soft agar, in vitro invasion assay in Boyden chambers, as well as zymography and Western Blot experiment were used to analyze expression of MMPs and in vitro behavior of tumor cells before and after gene transfection. RESULTS: In the presence of exogenous tetracycline, the expression of the transfected MMP-9 were under detectable level and no significant changes in cell behaviors were found when compared with vector-transfected control cells. But when the tetracycline was withdrew from the medium, the expression and activity of MMP-9 were significantly increased. The capacity of in vitro growth, colony forming ability in soft agar, invasion through Matrigel were enhanced remarkably. CONCLUSION: Transfection of sense MMP-9 can enhance growth and invasion of melanoma cells, further confirming its important role in tumor invasion and metastasis.

Cell Division↗
PubMed2005

[Correlations of serous levels of matrix metalloproteinases (MMP-2 and MMP-9) to invasion and metastasis of papillary thyroid carcinoma].

BACKGROUND & OBJECTIVE: Papillary thyroid carcinoma is a common carcinoma in thyroid without ideal hematological biomarkers to indicate its biological feature. This study was to explore the correlation of serous levels of matrix metalloproteinases (MMP-2 and MMP-9) to invasion and metastasis of papillary thyroid carcinoma. METHODS: Serous levels of MMP-2 and MMP-9 of 74 patients with pathologically confirmed papillary thyroid carcinoma were measured by zymography. All patients were treated with modified radical operation in the Second Affiliated Hospital of Wenzhou Medical College from 1999 to 2003. RESULTS: Serous levels of activated MMP-2 and MMP-9 were significantly higher in patients with lymph node metastases than in patients without lymph node metastases (71.9+/-11.7 vs. 35.2+/-6.6, P < 0.001; 15.5+/-6.1 vs. 7.3+/-2.3, P < 0.001), and were significantly higher in patients with carcinoma invaded in and through integument than in patients with carcinoma invaded within integument (70.5+/-13.0 vs. 35.4+/-7.9, P < 0.001; 14.7+/-6.1 vs. 8.0+/-4.2, P < 0.001). There was no significant difference in serous levels of activated MMP-2 and MMP-9 between patients with carcinoma diameter of > or =1 cm and < 1 cm (55.4+/-20.4 vs. 59.3+/-20.8, 10.8+/-5.7 vs. 13.7+/-6.8). There was also no significant difference in serous levels of total MMP-2 and MMP-9 between every 2 groups mentioned above (P > 0.05). CONCLUSION: Serous levels of activated MMP-2 and MMP-9 relate with invasion and metastasis of papillary thyroid carcinoma, but not relate with tumor size.

Adolescent↗
PubMed1998

Membrane-type matrix metalloproteinases in human dermal microvascular endothelial cells: expression and morphogenetic correlation.

Membrane-type matrix metalloproteinases (MT-MMP) activate the zymogen form of MMP-2/Gelatinase A on cell surfaces and are expressed in invasive tumors. We sought to identify and characterize MT-MMP in a non-malignant cell type that undergoes a physiologic and reversible invasive phenotype during angiogenesis. Human dermal microvascular endothelial cells (HDMEC) were isolated from neonatal tissue and purified by anti-CD31 (PECAM) affinity beads. MT-MMP-1 and -3 transcripts were amplified by reverse transcriptase-polymerase chain reaction and northern blots showed a single 4.5 kB mRNA for MT-MMP-1 that was modulated by angiogenic factors and phorbol ester. Immunoblotting of reduced cellular extracts with different MT-MMP-1 antibodies showed the presence of the 63-65 kDa and 57-60 kDa forms, as well as additional forms at lower molecular weights. HDMEC membranes extracted with Triton X114 were incubated with gelatin-sepharose purified MMP-2 and MMP-9 to show activation of proenzymes. Pre-incubation of HDMEC with anti-MT-MMP-1 antibodies decreased proMMP-2 conversion activity only. The movement of HDMEC and the formation of tubule-like structures in three-dimensional collagen gels was markedly delayed by preincubation with the same anti-MT-MMP-1 antibodies. These results demonstrate the presence of MT-MMP in cutaneous microvascular cells in vitro. Modulation of these cell surface proteinases by angiogenic factors, demonstration of multiple processed forms, and specific attenuation of HDMEC morphogenetic patterns in three-dimensional collagen gels implicate their potential roles in the formation of new blood vessels in the skin.

Angiogenesis Inducing Agents↗