Membrane-type 1 matrix metalloproteinase (MT1-MMP) and vascular endothelial growth factor (VEGF) are two key molecules involved
in pericellular proteolysis and cell proliferation during tumor growth ...and angiogenesis. Our previous data showed that MT1-MMP
overexpression in human breast carcinoma MCF7 cells induced an up-regulation of VEGF expression. This effect was associated
in vivo with accelerated tumor growth and angiogenesis. We now provide evidence that MT1-MMP overexpression specifically affected
VEGF-A production and failed to influence that of other VEGF family members (VEGF, B, C, D, or PlGF) or their receptors. The
up-regulation of VEGF-A by MT1-MMP was related to an increased transcriptional activation rather than to a modification of
mRNA stability. It was blocked by synthetic MMP inhibitors, TIMP2, but not TIMP-1 and abolished by a partial deletion of the
catalytic domain or the cytoplasmic tail of MT1-MMP. Analysis of the signal transduction mechanisms demonstrated that MT1-MMP
acts through a signaling pathway involving Src tyrosine kinases. Thus, our results provide new insight into the mechanisms
of action of MT1-MMP during angiogenesis and suggest that the full enzymatic activity of MT1-MMP is required for a specific
up-regulation of VEGF-A through an activation of Src tyrosine kinase pathways.
Protected areas may be important refuges for large carnivores, but many are not large enough to sustain viable populations. Without sufficient dispersal between protected areas, large carnivore ...populations inside them are at risk of becoming genetically isolated and demographically vulnerable. In this study, we use the jaguar population in and around Emas National Park in the Brazilian Cerrado as a case study to evaluate the demographic sustainability of a large carnivore population within a small and potentially isolated protected area. We used camera trapping data and spatially explicit capture‐recapture models to estimate density and corresponding population size of jaguars in Emas National Park. We then used a matrix‐based age and sex structured stochastic population model to evaluate the demographic viability of jaguar populations across a range of population sizes, including those estimated for Emas. We detected 10 individual jaguars during our survey with a total of 74 detections. Our density estimation became unbiased using a buffer width of 30 km and produced a density of 0.17 jaguars per 100 km2. The estimated population sizes of 10–60 animals suffered extinction risks of 70–90% without net immigration. However, only a low number of immigrants were required to suppress extinction risk towards zero. Our density estimate for jaguars was lower than in previous studies, and our simulations suggested that this population may have a substantial extinction risk. Ensuring dispersal and connectivity outside of protected areas, through the implementation of habitat corridors, can greatly reduce this extinction risk, and we suggest that this scenario is potentially applicable to many other large carnivore populations.
We used camera trapping data and spatially explicit capture‐recapture models to estimate density and corresponding population size of jaguars in Emas National Park in Brazil. We followed this with a matrix‐based age and sex structured stochastic population model to evaluate the demographic viability of jaguar populations across a range of population sizes, highlighting a need for connectivity between the jaguar populations.
Angiogenesis, the formation of new vessels from pre-existing capillaries, is a fundamental physiological process which is also critical for the development of several pathological conditions; thus a ...diminished angiogenic response is related to ischemic disorders, whereas increased angiogenesis is associated with tumorigenesis and chronic inflammatory diseases. New ways of modulating angiogenesis therefore have potential in the treatment of these diseases. During angiogenesis, normally quiescent endothelial cells (ECs) become migratory and invade the surrounding tissue. To do this, they require a specific enzyme machinery to degrade the tissue barriers presented by the basement membranes and the interstitial matrix. This function is supplied by matrix metalloproteinase (MMP) proteins, a large family of enzymes responsible for degrading a variety of extracellular matrix (ECM) components and for modulating the bioactivity of transmembrane receptors and soluble factors. In this review we examine the participation of MMPs--in particular membrane type 1-matrix metalloproteinase (MT1-MMP)--in the different steps of angiogenesis, and discuss the mechanisms of regulation of MT1-MMP in ECs. Finally, we explore the potential use of MMP inhibitors (MMPI) in the treatment of angiogenesis-related disease, with especial emphasis on novel approaches to the inhibition of MT1-MMP activity in ECs.
Aims Our objective was to test whether progenitor cell proliferation and differentiation potential may vary depending upon the disease of the donor. Methods and results Human cardiac mesoangioblasts ...were isolated from cardiac muscle biopsies of patients undergoing open heart surgery for correction of mitral regurgitation following an acute myocardial infarction (MR-MI) or correction of mitral and aortic regurgitation with ensuing left ventricular hypertrophy (MAR-LVH). The cells express surface markers and cardiac genes similar to mouse cardiac mesoangioblasts; they have limited self-renewing and clonogenic activity and are committed mainly to cardiogenesis. Although cardiac differentiation can be induced by 5-azacytidine or by co-culture with rat neonatal cardiomyocytes, human cells do not contract spontaneously like their mouse counterparts. When locally injected in the infarcted myocardium of immunodeficient mice, cardiac mesoangioblasts generate a chimeric heart that contains human myocytes and some capillaries; likewise, they colonize chick embryo hearts when transplanted in ovo. At variance with cells from patients with MR-MI, when isolation was performed on biopsies from MAR-LVH, cells could be isolated in much lower numbers, proliferated less extensively and failed to differentiate. Conclusion Cardiac mesoangioblasts are present in the human heart but this endogenous progenitor population is progressively exhausted, possibly by continuous and inefficient regeneration attempts.
Different cardiac stem/progenitor cells have been recently identified in the post-natal heart. We describe here the identification, clonal expansion and characterization of self-renewing progenitors ...that differ from those previously described for high spontaneous cardiac differentiation. Unique coexpression of endothelial and pericyte markers identify these cells as cardiac mesoangioblasts and allow prospective isolation and clonal expansion from the juvenile mouse ventricle. Cardiac mesoangioblasts express many cardiac transcription factors and spontaneously differentiate into beating cardiomyocytes that assemble mature sarcomeres and express typical cardiac ion channels. Cells similarly isolated from the atrium do not spontaneously differentiate. When injected into the ventricle after coronary artery ligation, cardiac mesoangioblasts efficiently generate new myocardium in the peripheral area of the necrotic zone, as they do when grafted in the embryonic chick heart. These data identify cardiac mesoangioblasts as committed progenitors, downstream of earlier stem/progenitor cells and suitable for the cell therapy of a subset of juvenile cardiac diseases.
Hepatocellular carcinoma is strongly associated with chronic infection by the hepatitis B virus (HBV) and has poor prognosis due to intrahepatic metastasis. HBx is often the only HBV protein detected ...in hepatic tumor cells; however, its contribution to tumor invasion and metastasis has not been established so far. In this work, we show that HBx enhances tumor cell invasion, both in vivo and in vitro. The increased invasive capacity induced by HBx is mediated by an upregulation of membrane-type 1 matrix metalloproteinase (MT1-MMP) expression, which in turn activates matrix metalloproteinase-2. Induction of both MT1-MMP expression and cell invasion by HBx is dependent on cyclooxygenase-2 (COX-2) activity. In addition, HBx upregulates the expression of COX-2, which is mediated by the transcriptional activation of the COX-2 gene promoter in a nuclear factor of activated T cell-dependent (NF-AT-dependent) manner. These results demonstrate the ability of HBx to promote tumor cell invasion by a mechanism involving the upregulation of MT1-MMP and COX-2 and provide new insights into the mechanism of action of this viral protein and its involvement in tumor metastasis and recurrence of hepatocellular carcinoma.
Membrane type 1-matrix metalloprotease (MT1-MMP or MMP-14) is a major activator of pro-MMP-2 and is essential for skeletal development. We show here that it is required for branching morphogenesis of ...the submandibular gland but not the lung. Instead, in the lung, it is essential for postnatal development of alveolar septae. Lung development in
Mmp14−/− mice is arrested at the prealveolar stage with compensatory hyperinflation of immature saccules.
Mmp2−/− mice lacked comparable defects in the lung and submandibular gland, suggesting that MT1-MMP acts via mechanisms independent of pro-MMP-2 activation. Since the developmental defects in the lung are first manifest around the time of initial vascularization (E16.5), we investigated the behavior of pulmonary endothelial cells from
Mmp14+/+ and
Mmp14−/− mice. Endothelial cells from lungs of 1-week-old
Mmp14−/− mice show reduced migration and formation of three-dimensional structures on Matrigel. Since pulmonary septal development requires capillary growth, the underlying mechanism of pulmonary hypoplasia in
Mmp14−/− mice may be defective angiogenesis, supporting a model in which angiogenesis is a critical rate-limiting step for acquisition of pulmonary parenchymal mass.
Mortality rates from chronic kidney disease (CKD) have increased in the last decade. In this pre-specified analysis of the DAPA-CKD trial, we determined the effects of dapagliflozin on cardiovascular ...and non-cardiovascular causes of death.
DAPA-CKD was an international, randomized, placebo-controlled trial with a median of 2.4 years of follow-up. Eligible participants were adult patients with CKD, defined as a urinary albumin-to-creatinine ratio (UACR) 200-5000 mg/g and an estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2. All-cause mortality was a key secondary endpoint. Cardiovascular and non-cardiovascular death was adjudicated by an independent clinical events committee. The DAPA-CKD trial randomized participants to dapagliflozin 10 mg/day (n = 2152) or placebo (n = 2152). The mean age was 62 years, 33% were women, the mean eGFR was 43.1 mL/min/1.73 m2, and the median UACR was 949 mg/g. During follow-up, 247 (5.7%) patients died, of whom 91 (36.8%) died due to cardiovascular causes, 102 (41.3%) due to non-cardiovascular causes, and in 54 (21.9%) patients, the cause of death was undetermined. The relative risk reduction for all-cause mortality with dapagliflozin (31%, hazard ratio HR 95% confidence interval (CI) 0.69 0.53, 0.88; P = 0.003) was consistent across pre-specified subgroups. The effect on all-cause mortality was driven largely by a 46% relative risk reduction of non-cardiovascular death (HR 95% CI 0.54 0.36, 0.82). Deaths due to infections and malignancies were the most frequently occurring causes of non-cardiovascular deaths and were reduced with dapagliflozin vs. placebo.
In patients with CKD, dapagliflozin prolonged survival irrespective of baseline patient characteristics. The benefits were driven largely by reductions in non-cardiovascular death.
We analysed data from the Paediatric Difficult Intubation Registry examining the use of direct laryngoscopy and GlideScope® videolaryngoscopy.
Data collected by a multicentre, paediatric difficult ...intubation registry from 1295 patients were analysed. Rates of success and complications between direct laryngoscopy and GlideScope videolaryngoscopy were analysed.
Initial (464/877 = 53% vs 33/828 = 4%, Z-test = 22.2, P < 0.001) and eventual (720/877 = 82% vs. 174/828 = 21%, Z-test = 25.2, P < 0.001) success rates for GlideScope were significantly higher than direct laryngoscopy. Children weighing <10 kg had lower success rates with the GlideScope than the group as a whole. There were no differences in complication rates per attempt between direct laryngoscopy and GlideScope. The direct laryngoscopy group had more complications associated with the greater number of attempts needed to intubate. There were no increased risks of hypoxia or trauma with GlideScope use. Each additional attempt at intubation with either device resulted in a two-fold increase in complications (odds ratio: 2.0, 95% confidence interval: 1.5–2.5, P < 0.001).
During difficult tracheal intubation in children, direct laryngoscopy is an overly used technique with a low chance of success. GlideScope use was associated with a higher chance of success with no increased risk of complications. GlideScope use in children with difficult tracheal intubation has a lower success rate than in adults with difficult tracheal intubation. Children weighing less than 10 kilograms had lower success rates with either device. Attempts should be minimized with either device to decrease complications.
Efficient delivery of stem cells to heart regions is still a major problem for cell therapy. Here, we report experiments aimed to improve migration of mouse and human cardiac mesoangioblasts to the ...damaged heart. Cardiac mesoangioblasts were induced to transmigrate through the endothelium by factors released by cardiomyocytes or cytokines, among which stromal-derived factor 1 (SDF-1) was the most potent. Cardiac mesoangioblasts were also delivered into the left ventricular (LV) chamber of mice after coronary artery ligation (CAL), and their in vivo homing to the damaged heart was found to be quite modest. Pretreatment of cardiac mesoangioblasts with SDF-1 or transient expression of L-selectin induced a two- to three-fold increase in their transmigration and homing to the damaged heart. Therefore, combined pretreatment with SDF-1 and L-selectin generated modified cardiac mesoangioblasts, 50% of which, after injection into the LV chamber of mice early after CAL, home directly to the damaged free wall of the heart. Finally, modified mouse cardiac mesoangioblasts, injected into the LV chamber regenerate a larger surface of the ventricle in long-term experiments in comparison with their control counterparts. This study defines the requirements for efficient homing of cardiac mesoangioblasts to the damaged heart and offers a new potent tool to optimize efficiency of future cell therapy protocols for cardiovascular diseases.
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