[Role of AMP-activated protein kinase in the cardiovascular system].
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AMP-Activated Protein Kinases↗
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[Regulators of angiogenesis].
Endothelial cells lining the lumen of vessels are maintained in the quiescent state and play important physiological roles. Yet, they can be de-differentiated and become one of the most rapidly proliferating of all cell types when stimulated. Angiogenesis or neovascularization is defined as the formation of new capillary vessels from existent microvessels, which plays a major role in the evolvement of a vascular supply in tissue during development or remodeling and disease. Angiogenesis is believed to be regulated by the balance between inducers and inhibitors. In this review article, I will summarize the molecules that regulate the process of angiogenesis.
Angiogenesis Inducing Agents↗
Augmentation of demineralized bone matrix (DBM) mineralization by a synthetic growth factor mimetic.
These studies evaluated whether F2A4-K-NS, a peptide mimetic of FGF-2, could augment ectopic bone production following the subcutaneous implant of human demineralized bone matrix (DBM). DBM was formulated into a gel with and without F2A4-K-NS, and injected subcutaneously into athymic rats. After 28 days the resultant tissue was excised and fixed. The tissue was examined with soft X-rays and microcomputerized tomography (micro-CT), and by histological methods. Inclusion of F2A4-K-NS with DBM resulted in an increased mineral deposition as determined by soft X-ray and micro-CT analysis and von Kossa staining. DBM-containing tissues showed extensive mineralization compared to the carrier alone, which was poorly mineralized. The mineralization was qualitatively and quantitatively the most extensive in the samples containing F2A4-K-NS plus DBM. Additionally, the highest amount of von Kossa staining for calcium was observed in tissues from animals that had received DBM plus F2A4-K-NS. In these studies, 100 ng of peptide per 0.2 mL of injectable DBM gel generated the most optimal results. The synthetic peptide F2A4-K-NS augmented DBM-induced ectopic mineralization in athymic animals.
Animals↗
Distraction osteogenesis of the canine mandible: the impact of acute callus manipulation on vascularization and early bone formation.
PURPOSE: Manipulations of the newly created regenerate, using adjustable multiplanar devices during distraction osteogenesis or as a 1-step molding procedure at the end of the distraction process, may be necessary to correct the position of the mandible. Treatment of complex deformities may require preplanned major angulation provided by adjustable devices. We sought to assess the effects of molding the fresh regenerate on vascularization and early bone formation within clinically relevant dimensions. MATERIALS AND METHODS: Evaluation of the nature of the problem in mechanical terms was based on a geometrical model, its dimensions chosen with clinical relevance. Custom-made devices, allowing the simultaneous compression and stretching of a regenerate 10 mm long, were fixed bilaterally in the angular region of beagle mandibles (n = 14). Angulation of 20 degrees (n = 7) or 30 degrees (n = 7) was performed immediately after ending the lengthening period, and the animals were killed after a 7-day consolidation period. The vascular system was stained via intravital Procion red infusion and post mortem carbon ink (Deperussol P130; Degussa AG, Frankfurt, Germany) perfusion to assess possible damages. Qualitative and quantitative evaluations of the mineralized tissue were performed with contact radiography, quantified computed tomography, and histologic assessment. RESULTS: The only finding indicating mechanical forces acting on the regenerate was related to orientation of the collagenous fibers. Vascular damage was not observed. Mineralization patterns were identical in both the compressed and the stretched zone. The degree of angulation had no visible impact on early bone formation, even if compression and stretching of the regenerate at a range of 33% to 54% exceeds most clinical requirements. However, the amount of callus formation differed independent of the shaping angle, revealing parameters other than the degree of angulation to be important. CONCLUSIONS: Although the newly forming bone is highly sensitive to nonphysiologic strain during the lengthening process, a completed fresh regenerate, created by distraction osteogenesis, can be manipulated to a considerable extent without endangering early callus formation. Manipulation of the regenerates would provide a precise final result, minimizing the need for secondary corrections and diminishing treatment duration and costs.
Animals↗
Vascular-specific quantification in an in vivo Matrigel chamber angiogenesis assay.
The study of angiogenesis as a therapeutic target requires reliable in vivo assays that can provide physiologically relevant data. A murine in vivo Matrigel-based angiogenesis assay is presented here which includes the quantitative assessment of vascular-specific indicators of neovascularization. Matrigel containing 175 ng/ml bFGF is encapsulated in synthetic chambers which are implanted subcutaneously in C57/B16J mice. Ex vivo implants can be imaged to qualitatively view perfused vasculature within the chambers, or histologically processed to confirm the presence of vascular-specific tissue within the Matrigel. Viable cells are recovered from the excised chambers and quantified cytometrically using endothelial cell-specific markers CD34 and CD144, and for a marker of nucleated cells, Hoechst 33342. Thalidomide, 200 mg/kg/day, was tested using the assay and was found to inhibit angiogenesis by 46%. Angiogenesis inhibitors secreted by LL/M27 tumors were also characterized, where tumor-bearing mice showed a 73% inhibition of angiogenesis compared to tumor-free controls. Analysis of the number of nucleated cells in these samples failed to show a strong correlation with the number of endothelial cells, indicating that quantification of nonvascular-specific tissue in in vivo angiogenesis assays may not be sufficient. This new assay provides an objective, comprehensive determination of the vasculature-specific response of both endogenous and exogenous angiogenesis inhibitors in vivo, and also creates new opportunities for obtaining primary murine endothelial cells.
Angiogenesis Inhibitors↗
Soluble flt-1 and the angiopoietins in the development and regulation of placental vasculature.
One of the key roles of the placenta is to mediate exchange of oxygen, nutrients and waste products between the maternal and fetal circulations. While some nutrients are actively taken up, oxygen is passively transported (i.e. it moves down a simple concentration gradient). To ensure an adequate supply as gestation progresses, the vascular structures in the human placenta remodel to facilitate this transfer. Under conditions in which oxygen is limited, at high altitude for example, these adaptations become more pronounced. In placentae obtained from high altitude the mean diameter of vessels is increased and the number of perivascular cells (pericytes) is reduced. Pericytes play an important role in modulating endothelial cell function and in their absence the endothelial cells are sensitive to growth factor withdrawal. The vascular remodelling that occurs in normal pregnancy is in part mediated by soluble factors (some produced by pericytes) and the level of these may in turn be regulated by local oxygen tension. We have shown that the mRNAs encoding both angiopoietins are present in the placenta and both are regulated by local PO2. Ang-2 mRNA transcription is increased under reduced oxygen and the stability of Ang-1 mRNA is reduced under similar conditions. Thus the ratio of mRNAs encoding these antagonistic factors changes (in favour of Ang-2), in the placenta in response to a reduction in PO2. The adaptations seen in the placenta and the mechanism by which they are achieved may be generally applicable.
Adaptation, Physiological↗
Endothelial cells assemble into a 3-dimensional prevascular network in a bone tissue engineering construct.
To engineer tissues with clinically relevant dimensions, one must overcome the challenge of rapidly creating functional blood vessels to supply cells with oxygen and nutrients and to remove waste products. We tested the hypothesis that endothelial cells, cocultured with osteoprogenitor cells, can organize into a prevascular network in vitro. When cultured in a spheroid coculture model with human mesenchymal stem cells, human umbilical vein endothelial cells (HUVECs) form a 3-dimensional prevascular network within 10 days of in vitro culture. The formation of the prevascular network was promoted by seeding 2% or fewer HUVECs. Moreover, the addition of endothelial cells resulted in a 4-fold upregulation of the osteogenic marker alkaline phosphatase. The addition of mouse embryonic fibroblasts did not result in stabilization of the prevascular network. Upon implantation, the prevascular network developed further and structures including lumen could be seen regularly. However, anastomosis with the host vasculature was limited. We conclude that endothelial cells are able to form a 3-dimensional (3D) prevascular network in vitro in a bone tissue engineering setting. This finding is a strong indication that in vitro prevascularization is a promising strategy to improve implant vascularization in bone tissue engineering.
Alkaline Phosphatase↗
Rat mandibular distraction osteogenesis: latency, rate, and rhythm determine the adaptive response.
Distraction osteogenesis is a well-established technique of endogenous tissue engineering. The biomechanical factors thought to affect the quality of the distraction regenerate include the latency, rate, rhythm, and consolidation period. In an effort to understand the impact of these parameters on regenerate bone formation, this study was designed to decipher the most adaptive response in a rat model of mandibular distraction osteogenesis. Ninety-six adult Sprague-Dawley rats were divided into 16 subgroups (n = 6 per subgroup) based on variations in the distraction parameters (i.e., latency, rate, and rhythm). After a 28-day consolidation period, the mandibles were harvested, decalcified, and sectioned. A standardized histologic ranking system was used to evaluate the effect of each protocol on the adaptive response of the regenerate bone. In this study, we have demonstrated that the latency period dramatically affects the success of distraction osteogenesis. Furthermore, distraction rates up to 0.50 mm per day stimulated excellent regenerate bone formation, whereas greater distraction rates produced a fibrous union. Finally, higher frequency distraction (i.e., increased rhythm) appeared to accelerate regenerate bone formation. We believe that defining the critical parameters of this model will improve future analysis of gene expression during rat mandibular distraction osteogenesis and may facilitate the development of biologically based strategies designed to enhance regenerate bone formation.
Adaptation, Physiological↗
Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway.
Postnatal growth of the heart is primarily achieved through hypertrophy of individual myocytes. Cardiac growth observed in athletes represents adaptive or physiological hypertrophy, whereas cardiac growth observed in patients with hypertension or valvular heart diseases is called maladaptive or pathological hypertrophy. These two types of hypertrophy are morphologically, functionally, and molecularly distinct from each other. The serine/threonine protein kinase Akt is activated by various extracellular stimuli in a phosphatidylinositol-3 kinase-dependent manner and regulates multiple aspects of cellular functions including survival, growth and metabolism. In this review we will discuss the role of the Akt signaling pathway in the heart, focusing on the regulation of cardiac growth, contractile function, and coronary angiogenesis. How this signaling pathway contributes to the development of physiological/pathological hypertrophy and heart failure will also be discussed.
Adaptation, Physiological↗
Age is no barrier to muscle structural, biochemical and angiogenic adaptations to training up to 24 months in female rats.
Ageing is associated with reduced transport and utilization of O(2), diminishing exercise tolerance. Reductions may occur in cardiac output (delivery), and skeletal muscle oxidative capacity (utilization). To determine the reversibility of the declines in the muscular determinants of these limitations, skeletal muscle morphological, angiogenic and biochemical responses to acute exercise and endurance training were investigated in female Fischer 344 rats (n = 42; seven groups of six rats) aged 6 (Y) and 24 (O) months compared with resting untrained controls (Y(C), O(C)). Treadmill training lasted 8 weeks (10 deg incline, 1 h per day, 5 days per week). Two groups ran at maximum tolerated speeds (Y(TR), O(TR)), while an additional Y group (Y(TM)) trained at O(TR) speed. There was no effect of age on vascular endothelial growth factor gene expression in gastrocnemius muscles after acute exercise. Similarly, age did not impair the effects of training, with increases (P < 0.05; +/-s.e.m.) occurring in all of the following: 1 h exercise running speed (Y(TR) 92 +/- 4% versus O(TR) 140 +/- 25%); citrate synthase (Y(TR) 37 +/- 8% versus O(TR) 97 +/- 33%) and beta-hydroxyacyl-CoA-dehydrogenase (Y(TR) 31 +/- 7%, versus O(TR) 72 +/- 24%) activities; and capillary-to-fibre ratio (Y(TR) 5.2 +/- 0.2% versus O(TR) 8.1 +/- 0.2%). However, Y(TM) muscle was unchanged in each measure compared with Y(C). In conclusion, these muscular responses to training were (1) not reduced by ageing, but (2) dependent on relative and not absolute work rate, since, at the same speed, O(TR) rats showed greater changes than Y(TM). Therefore, increases in exercise tolerance and muscle adaptations are not impaired in female rats up to 24 months of age, and require a smaller absolute exercise stimulus (than young) to be manifest.
3-Hydroxyacyl CoA Dehydrogenases↗
Highly effective compensatory mechanisms in a 76-year-old man with a coarctation of the aorta.
We present a man who was diagnosed with coarctation of the aorta (CA) at the age of 76. He had developed an extensive collateral circulation for maintaining the circulation below the CA. This compensatory mechanism was highly effective, since the patient had remained asymptomatic and in good health during most of his life. He died from intrahospitalary pneumonia, unrelated to CA. Long-term survival in patients with untreated CA is exceptional, with only 11 patients living into their 70s being previously reported. A review of these cases is included.
Adaptation, Physiological↗
Functional characterization of the spontaneously transformed human umbilical vein endothelial cell line ECV304: use in an in vitro model of angiogenesis.
To gain insight into the role of the endothelial cell during the pathophysiology of the angiogenic response, investigators have isolated micro- and macrovascular endothelial cells from a wide range of both animal and human vessels, including the umbilical vein. Human umbilical vein endothelial cells (HUVECs) isolated from umbilical cords remain a readily available and popular source of endothelial cell. However, the isolation and culture of these cells have several disadvantages, including the risk of infection, exogenous growth factor requirement, and low proliferative capacity. The heterogeneity of endothelial cells from different vascular beds as well as the heterogeneity between HUVEC isolates from different cords can make the critical interpretation of results difficult. ECV304 is a unique spontaneously transformed human umbilical vein endothelial cell line. In this report, the novel use of ECV304 cells as an alternative to HUVECs in an in vitro model of angiogenesis using the reconstituted basement membrane extract (Matrigel) was investigated. ECV304 cells were characterized immunohistochemically and their angiogenic behavior on Matrigel was analyzed functionally by phase-contrast, electron, and time-lapse video microscopy. ECV304 cells had several practical advantages over HUVEC culture and in contrast to HUVECs, ECV304 cells exhibited an enhanced and highly reproducible capacity for in vitro angiogenesis. However, several differentiated functions were lost or reduced in the ECV304 cell line which also exhibited anomalous cytokeratin expression. ECV304 cells may provide novel insights into the mechanisms governing angiogenesis under both normal physiological and pathological conditions.
Animals↗
Mechanical signalling and angiogenesis. The integration of cell-extracellular matrix couplings.
In vitro angiogenesis assays have shown that the couplings between fibrin gel and cell traction forces trigger biogel pre-patterning, consisting, in the formation of lacunae which evolve toward capillary-like structures (CLS) networks. Depending on the experimental conditions (number of seeded cells, gel elasticity,...), this pre-patterning can be enhanced or inhibited. A theoretical model based on a description of the cell-biogel biochemical and mechanical interactions is proposed as a basis for understanding how integrating these interactions can lead to the pre-patterning of the biogel. We showed that the critical parameter values corresponding to the bifurcation of the model solutions correspond to threshold values of the experimental variables. Furthermore, simulations of the mechanocellular model give rise to dynamic remodelling patterns of the biogel which are in good agreement both with the lacunae morphologies and with the time and space scales derived from the in vitro angiogenesis assays. Special attention has been paid in the simulations to cell proteolytic activity and to the amplitude of cell traction forces. We finally discussed how modelling guided experiments can be inferred from these results.
Biomechanical Phenomena↗
NADPH oxidases in cardiovascular health and disease.
Increased oxidative stress plays an important role in the pathophysiology of cardiovascular diseases such as hypertension, atherosclerosis, diabetes, cardiac hypertrophy, heart failure, and ischemia-reperfusion. Although several sources of reactive oxygen species (ROS) may be involved, a family of NADPH oxidases appears to be especially important for redox signaling and may be amenable to specific therapeutic targeting. These include the prototypic Nox2 isoform-based NADPH oxidase, which was first characterized in neutrophils, as well as other NADPH oxidases such as Nox1 and Nox4. These Nox isoforms are expressed in a cell- and tissue-specific fashion, are subject to independent activation and regulation, and may subserve distinct functions. This article reviews the potential roles of NADPH oxidases in both cardiovascular physiological processes (such as the regulation of vascular tone and oxygen sensing) and pathophysiological processes such as endothelial dysfunction, inflammation, hypertrophy, apoptosis, migration, angiogenesis, and vascular and cardiac remodeling. The complexity of regulation of NADPH oxidases in these conditions may provide the possibility of targeted therapeutic manipulation in a cell-, tissue- and/or pathway-specific manner at appropriate points in the disease process.
Animals↗
Differences in local environment determine the site of physiological angiogenesis in rat skeletal muscle.
The specificity in location of angiogenesis to either glycolytic or oxidative fibre types, or muscle regions, was examined in the tibialis anterior (TA) and extensor digitorum longus (EDL) muscles of rat. Angiogenesis was induced by mechanical means either with (chronic muscle stimulation) or without (muscle stretch by overload) changes in blood flow, treatments which invoked only minor changes in fibre type and fibre size. Proliferation estimated by PCNA labelling of cells co-localised with capillaries was very rare in control muscles, where it occurred mainly in the glycolytic regions, but was increased in both models of angiogenesis. However, when labelled capillaries were scored according to the type of surrounding fibres, only muscle stimulation significantly accentuated proliferation of capillaries surrounded by glycolytic fibres. We conclude that while mechanical stimuli are important for proliferation in glycolytic regions in both models, capillary growth occurs specifically around glycolytic fibres in that region when the angiogenic stimulus includes increased blood flow and/or increased metabolic demand.
Adaptation, Physiological↗
Mechanical signaling and the cellular response to extracellular matrix in angiogenesis and cardiovascular physiology.
Great advances have been made in the identification of the soluble angiogenic factors, insoluble extracellular matrix (ECM) molecules, and receptor signaling pathways that mediate control of angiogenesis--the growth of blood capillaries. This review focuses on work that explores how endothelial cells integrate these chemical signals with mechanical cues from their local tissue microenvironment so as to produce functional capillary networks that exhibit specialized form as well as function. These studies have revealed that ECM governs whether an endothelial cell will switch between growth, differentiation, motility, or apoptosis programs in response to a soluble stimulus based on its ability to mechanically resist cell tractional forces and thereby produce cell and cytoskeletal distortion. Transmembrane integrin receptors play a key role in this mechanochemical transduction process because they both organize a cytoskeletal signaling complex within the focal adhesion and preferentially focus mechanical forces on this site. Molecular filaments within the internal cytoskeleton--microfilaments, microtubules, and intermediate filaments--also contribute to the cell's structural and functional response to mechanical stress through their role as discrete support elements within a tensegrity-stabilized cytoskeletal array. Importantly, a similar form of mechanical control also has been shown to be involved in the regulation of contractility in vascular smooth muscle cells and cardiac myocytes. Thus, the mechanism by which cells perform mechanochemical transduction and the implications of these findings for morphogenetic control are discussed in the wider context of vascular development and cardiovascular physiology.
Animals↗
Brunner's glands: a structural, histochemical and pathological profile.
Brunner's glands are unique to mammalian species and in eutherians are confined primarily to the submucosa of the proximal duodenum. In the majority of species examined, they begin at the gastrointestinal junction and extend for variable distances distally in the wall of the proximal small intestine. Ducts of individual glands empty either directly into the intestinal lumen or unite with overlying intestinal glands (crypts of Lieberkühn) dependent on the species. Secretory units of Brunner's glands consist of epithelial tubules that show frequent distal branchings. The secretory units, with the exception of those found in rabbits and horses, consist primarily of a mucin producing cell type. However, other cell types normally associated with the overlying intestinal epithelium may be encountered scattered within the secretory units reflecting the developmental origin of these glands. Secretion from Brunner's glands contributes to a layer of mucus that forms a slippery, viscoelastic gel that lubricates the mucosal lining of the proximal intestinal tract. The unique capacity of this mucus layer to protect delicate underlying epithelial surfaces is due primarily to the gel-forming properties of its glycoprotein molecules. Mucin glycoproteins produced by Brunner's glands consist primarily but not exclusively of O-linked oligosaccharides attached to the central protein core of the glycoprotein molecule. Human Brunner's glands produce class III mucin glycoproteins and are thought to be the product of mucin gene MUC6 which is assigned to chromosome 11 (11p15-11p15.5 chromosome region). In addition to mucin glycoproteins and a limited amount of bicarbonate, numerous additional factors (epidermal growth factor, trefoil peptides, bactericidal factors, proteinase inhibitors, and surface-active lipids) have been identified within the secretory product of Brunner's glands. These factors, incorporated into the mucus layer, guard against the degradation of this protective barrier and underlying mucosa by gastric acid, pancreatic enzymes, and other surface active agents associated with this region. Yet other factors produced by Brunner's glands function to provide active and passive immunological defense mechanisms, promote cellular proliferation and differentiation, as well as contribute factors that elevate the pH of luminal contents of this region by promoting secretion of the intestinal mucosa, pancreatic secretion and gall bladder contraction. Additional insights concerning the role of Brunner's glands in the mammalian gastrointestinal tract as well as their possible evolution in this class of vertebrates have been gained from a basic understanding of their pathobiology.
Adaptation, Physiological↗
VEGF receptor signalling - in control of vascular function.
Vascular endothelial growth-factor receptors (VEGFRs) regulate the cardiovascular system. VEGFR1 is required for the recruitment of haematopoietic precursors and migration of monocytes and macrophages, whereas VEGFR2 and VEGFR3 are essential for the functions of vascular endothelial and lymphendothelial cells, respectively. Recent insights have shed light onto VEGFR signal transduction and the interplay between different VEGFRs and VEGF co-receptors in development, adult physiology and disease.
Animals↗