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PubMed1996

Advanced hypertensive heart disease in spontaneously hypertensive rats. Lisinopril-mediated regression of myocardial fibrosis.

Left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHR) is accompanied by a structural remodeling of the myocardium that includes myocyte hypertrophy and interstitial and perivascular fibrosis of intramyocardial coronary arteries. The structural abnormalities related to fibrous tissue accumulation lead to increased myocardial diastolic stiffness and ultimately impaired systolic function of the left ventricle. It has been shown in 14-week-old SHR with early hypertensive heart disease that myocardial fibrosis could be reversed and myocardial diastolic stiffness normalized by 12-week treatment with the angiotensin-converting enzyme inhibitor lisinopril. Whether such functional defects of the myocardium, based on adverse structural changes, are also reversible in advanced hypertensive heart disease has been questioned. Therefore, we treated 78-week-old male SHR that had chronic hypertension and advanced LVH with severe myocardial fibrosis and age- and sex-matched normotensive Wistar-Kyoto rats (WKY) with 20 mg/kg per day oral lisinopril for 8 months. Compared with untreated SHR or WKY, we found the following: (1) Systolic arterial pressure was normalized (P < .025) and LVH completely reversed (P < .025) in SHR, with no significant reduction in systolic arterial pressure or left ventricular mass in WKY; (2) morphometrically determined myocardial fibrosis in SHR was significantly reversed (P < .025) and associated with improved diastolic stiffness (P < .05), which was measured in the isolated heart by calculation of the stiffness constant of the myocardium; no significant changes occurred in WKY; (3) reversal of myocardial fibrosis was accompanied by an increase (P < .025) in myocardial matrix metalloproteinase 1 activity determined by degradation of [14C]collagen with myocardial tissue extracts after trypsin activation of myocardial promatrix metalloproteinase 1; matrix metalloproteinase 1 activity remained unchanged in WKY treated with lisinopril; and (4) systolic dysfunction, measured by a significantly (P < .025) diminished slope of the systolic stress-strain relation under isovolumic conditions of the left ventricle, was found in 110-week-old SHR, and it could be prevented by lisinopril treatment. Thus, long-term angiotensin-converting enzyme inhibition with lisinopril normalized arterial pressure and LVH, reversed myocardial fibrosis, and improved abnormal myocardial diastolic stiffness in advanced hypertensive heart disease in SHR. In addition, systolic dysfunction of the left ventricle could be prevented. The fibrolytic response to lisinopril was at least partly due to enhanced collagen degradation by activation of tissue matrix metalloproteinase 1.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Measurements of mechanical properties of the blastula wall reveal which hypothesized mechanisms of primary invagination are physically plausible in the sea urchin Strongylocentrotus purpuratus.

Computer simulations showed that the elastic modulus of the cell layer relative to the elastic modulus of the extracellular layers predicted the effectiveness of different force-generating mechanisms for sea urchin primary invagination [L. A. Davidson, M. A. R. Koehl, R. Keller, and G. F. Oster (1995) Development 121, 2005-2018]. Here, we measured the composite elastic modulus of the cellular and extracellular matrix layers in the blastula wall of Strongylocentrotus purpuratus embryos at the mesenchyme blastula stage. Combined, these two layers exhibit a viscoelastic response with an initial stiffness ranging from 600 to 2300 Pa. To identify the cellular structures responsible for this stiffness we disrupted these structures and correlated the resulting lesions to changes in the elastic modulus. We treated embryos with cytochalasin D to disrupt the actin-based cytoskeleton, nocodazole to disrupt the microtubule-based cytoskeleton, and a gentle glycine extraction to disrupt the apical extracellular matrix (ECM). Embryos treated less than 60 min in cytochalasin D showed no change in their time-dependent elastic modulus even though F-actin was severely disrupted. Similarly, nocodazole had no effect on the elastic modulus even as the microtubules were severely disrupted. However, glycine extraction resulted in a 40 to 50% decrease in the elastic modulus along with a dramatic reduction in the hyalin protein at the apical ECM, thus implicating the apical ECM as a major mechanical component of the blastula wall. This finding bears on the mechanical plausibility of several models for primary invagination.

Actins↗
PubMed1990

Material properties and structure-function relationships in the menisci.

The menisci serve several important biomechanical functions in the knee. They distribute stresses over a broad area of articular cartilage, absorb shocks during dynamic loading, and probably assist in joint lubrication. These functions enhance the ability of articular cartilage to provide a smooth, near-frictionless articulation and to distribute loads evenly to the underlying bone of the femur and tibia. In addition, the menisci provide stability to the injured knee when the cruciate ligaments or other primary stabilizers are deficient. The ability to perform these mechanical functions is based on the intrinsic material properties of the menisci as well as their gross anatomic structure and attachments. The material properties of the menisci are determined by their biochemical composition and, perhaps more important, by the organization and interactions of the major tissue constituents: water, proteoglycan, and collagen. Interactions among the important constituents of the fibrocartilage matrix cause meniscal tissue to behave as a fiber-reinforced, porous, permeable composite material similar to articular cartilage, in which frictional drag caused by fluid flow governs its response to dynamic loading. The menisci are one-half as stiff in compression and dissipate more energy under dynamic loading than articular cartilage. Energy dissipation, or shock absorption, by the menisci is the result of high frictional drag caused by low permeability of the matrix, which is about one-sixth as permeable as articular cartilage. The dynamic shear modulus of meniscal tissue is only one-fourth to one-sixth as great as that of articular cartilage. The coarse, circumferential Type I collagen fiber bundles of the meniscus give the tissue great tensile stiffness (range, 100-300 megapascals) and strength. The highly oriented collagen ultrastructure of the menisci makes the tissue anisotropic in tension, compression, and shear and appears to dominate its behavior under all loading conditions.

Collagen↗
PubMed2006

Role of T lymphocytes in hypertension-induced cardiac extracellular matrix remodeling.

Cardiac remodeling in response to pressure overload involves reorganization of the myocytes and extracellular matrix (ECM). Neurohormonal pathways have been described as effector pathways in left ventricular ECM reorganization in response to pressure overload; we now are assessing the role of the T lymphocyte in this process. Mice with defined differences in T-lymphocyte function (C57BL/6 SCID, C57BL/6 WT, and BALB/c) were treated with 50 mg/L of N(G)-nitro-l-arginine methyl ester in their drinking water for 30 days. The immune function of C57BL/6 WT mice was T-helper type 1 (TH1), BALB/c was TH2, and C57BL/6 SCID was null. The arterial blood pressure increased by 30% in all of the strains of mice. However, ventricular stiffness significantly decreased in the C57 SCID, significantly increased in the BALB/c, and did not change in the C57 WT. The characterization of matrix metalloproteinase induction and activation on day 30 was associated with T-lymphocyte function. The total cardiac fibrillar collagen, percentage of fibrillar collagen cross-linking, and the activity of the cross-linking enzyme lysyl oxidase-like-3 (LOXL-3) significantly decreased in the C57 SCID, significantly increased in the BALB/c, and did not change in the C57 WT. This study revealed that the LOXL-3 pathway, namely, gene expression, enzymatic activities, and LOXL-3-mediated collagen cross-linking, was associated with ventricular stiffness and incongruence with lymphocyte function. These data support the concept that the T lymphocytes may play a fundamental regulatory role in cardiac ECM composition through modulation of collagen synthesis, degradation, and cross-linking.

Amino Acid Oxidoreductases↗
PubMed2006

Homocysteine-induced myofibroblast differentiation in mouse aortic endothelial cells.

Differentiation of myofibroblast, as evidenced by alpha-smooth muscle actin (alpha-SMA) expression, is largely mediated by transforming growth factor-beta1 (TGF-beta1). This mechanism often follows inflammatory events such as endothelial damage due to oxidative stress, which can further leads to vascular thickening, stiffness, and fibrosis. We hypothesized that hyperhomocysteinemia (HHcy)-induced oxidative stress lead to vascular stiffness, in part due to endothelial-myofibroblast differentiation and alteration of collagen homeostasis in the extracellular matrix (ECM). We tested our hypothesis in vitro using mouse aortic endothelial cells (MAEC). Our result shows that Hcy induces alpha-SMA and collagen type-1 expression in MAEC as evidenced by immunoblot and confocal imaging. RT-PCR shows robust increase of alpha-SMA and collagen type-1 mRNA level in Hcy-induced condition. We demonstrated that Hcy induces autophosphorylation of focal adhesion kinase (FAK) (a member of the protein tyrosine kinase (PTK) family) at Tyr-397. PP2 (general PTK inhibitor) as well as FAK siRNA abrogates Hcy-mediated alpha-SMA formation. In addition to that, Hcy-mediated TGF-beta1 induction was inhibited by TGF-beta R1 kinase inhibitor II (ALK5 inhibitor II) and attenuated FAK phosphorylation and alpha-SMA expression. Furthermore, we showed that Hcy activates ERK-44/42 (extracellular signal-regulated kinase) pathway and augments collagen type-1 deposition. Studies with pharmacological ERK blocker, PD98059 and ERK siRNA attenuated ERK-44/42 phosphorylation and collagen type-1 synthesis. Taken together our results demonstrate that Hcy-mediated TGF-beta1 upregulation triggers endothelial-myofibroblast differentiation secondary to FAK phosphorylation and that Hcy-induced ERK activation is involved in ECM remodeling by altering collagen type-1 homeostasis.

Actins↗
PubMed2001

The effects of cross-linking of collagen-glycosaminoglycan scaffolds on compressive stiffness, chondrocyte-mediated contraction, proliferation and biosynthesis.

The healing of articular cartilage defects may be improved by the use of implantable three-dimensional matrices. The present study investigated the effects of four cross-linking methods on the compressive stiffness of collagen-glycosaminoglycan (CG) matrices and the interaction between adult canine articular chondrocytes and the matrix: dehydrothermal treatment (DHT), ultraviolet irradiation (UV), glutaraldehyde treatment (GTA), and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDAC). The degree and kinetics of chondrocyte-mediated contraction, chondrocyte proliferation, and protein and glycosaminoglycan synthesis were evaluated over a four-week period in vitro. Cell-mediated contraction of the matrices varied with cross-linking: the most compliant DHT and UV matrices contracted the most (60% reduction in matrix diameter) and stiffest EDAC matrices contracted the least (30% reduction in matrix diameter). All cross-linking protocols permitted cell proliferation and matrix synthesis as measured by DNA content and radiolabeled sulfate and proline incorporation, respectively. During the first week in culture, a lower level of proliferation was seen in the GTA matrices but over the four-week culture period, the GTA and EDAC matrices provided for the greatest cell proliferation. On day 2, there was a significantly lower rate of 3H-proline incorporation in the GTA matrices (p<0.003) although at later time points, the EDAC and GTA matrices exhibited the highest levels of matrix synthesis. With regard to cartilage-specific matrix molecule synthesis, immunohistochemistry revealed a greater amount of type II collagen in DHT and UV matrices at the early time points. These findings serve as a foundation for future studies of tissue engineering of articular cartilage and the association of chondrocyte contraction and the processes of mitosis and biosynthesis.

Animals↗
PubMed1999

Direct observations of the mechanical behaviors of the cytoskeleton in living fibroblasts.

Cytoskeletal proteins tagged with green fluorescent protein were used to directly visualize the mechanical role of the cytoskeleton in determining cell shape. Rat embryo (REF 52) fibroblasts were deformed using glass needles either uncoated for purely physical manipulations, or coated with laminin to induce attachment to the cell surface. Cells responded to uncoated probes in accordance with a three-layer model in which a highly elastic nucleus is surrounded by cytoplasmic microtubules that behave as a jelly-like viscoelastic fluid. The third, outermost cortical layer is an elastic shell under sustained tension. Adhesive, laminin-coated needles caused focal recruitment of actin filaments to the contacted surface region and increased the cortical layer stiffness. This direct visualization of actin recruitment confirms a widely postulated model for mechanical connections between extracellular matrix proteins and the actin cytoskeleton. Cells tethered to laminin-treated needles strongly resisted elongation by actively contracting. Whether using uncoated probes to apply simple deformations or laminin-coated probes to induce surface-to-cytoskeleton interaction we observed that experimentally applied forces produced exclusively local responses by both the actin and microtubule cytoskeleton. This local accomodation and dissipation of force is inconsistent with the proposal that cellular tensegrity determines cell shape.

Actins↗
PubMed2006

Cellular and matrix mechanics of bioartificial tissues during continuous cyclic stretch.

Bioartificial tissues are useful model systems for studying cell and extra-cellular matrix mechanics. These tissues provide a 3D environment for cells and allow tissue components to be easily modified and quantified. In this study, we fabricated bioartificial tissue rings from a 1 ml solution containing one million cardiac fibroblasts and 1 mg collagen. After 8 days, rings compacted to <1% of original volume and cell number increased 2.4 fold. We initiated continuous cyclic stretching of the rings after 2, 4, or 8 days of incubation, while monitoring the tissue forces. Peak tissue force during each cycle decreased rapidly after initiating stretch, followed by further slow decline. We added 2 microM Cytochalasin-D to some rings prior to initiation of stretch to determine the force contributed by the matrix. Cell force was estimated by subtracting matrix force from tissue force. After 12 h, matrix force-strain curves were highly nonlinear. Cell force-strain curves were linear during loading and showed hysteresis indicating viscoelastic behavior. Cell stiffness increased with stretching frequency from 0.001-0.25 Hz. Cell stiffness decreased with stretch amplitude (5-25%) at 0.1 Hz. The trends in cell stiffness do not fit simple viscoelastic models previously proposed, and suggest possible strain-amplitude related changes during cyclic stretch.

Animals↗
PubMed1997

Mechanical and material properties of the subchondral bone plate from the femoral head of patients with osteoarthritis or osteoporosis.

OBJECTIVE: To determine the material properties of the subchondral bone plate in patients with osteoarthritis or osteoporosis. METHODS: Femoral heads were obtained after surgical removal from age and sex matched groups of patients with either osteoporosis (OP), after a fractured neck of femur, or osteoarthritis (OA) and compared with a normal group. The mechanical stiffness, density, and composition of the subchondral bone plate from sites selected to represent areas of heavy, intermittent, and light loading were measured. RESULTS: Overall, OP bone was the least stiff and dense, followed by OA bone; normal bone was stiffer and more dense (p < 0.05). Though OP bone contained less mineral, the organic and water contents were increased in proportion suggesting no change in the relative amount of organic matrix. OA bone was also hypomineralised (p < 0.05) but had different organic and water fractions suggesting a defect in the matrix. Site variation of most properties was small, though across all the groups the superior region was significantly stiffer than the inferior. CONCLUSION: This study shows that subchondral bone plate is less stiff than normal in both OP and OA and so cannot, by itself, explain the preserving of the overlying cartilage in OP while aiding its destruction in OA. However, the subchondral bone plate is only one part of the bony structure of the femoral head and changes in the cancellous bone need to be considered. The generalised changes in bone composition found in patients with OA support the hypothesis that the disease could involve the bone in the primary pathogenesis.

Aged↗
PubMed2006

Correlation between impairment and motor performance during reaching tasks in subjects with spastic hemiparesis.

OBJECTIVE: The main purposes of this study were to examine, in subjects with chronic hemiparesis following a stroke: (i) the correlations between tests of muscle tone, stiffness, spasticity, paresis and co-contraction, and (ii) the correlations of these tests and measurements of impairment to upper extremity motor performance. DESIGN: Prospective, cross-sectional, correlation matrix using sample of convenience. SUBJECTS: Thirteen subjects with chronic hemiparesis secondary to a cerebrovascular accident (stroke) were tested. METHODS: Subjects were assessed using the Fugl-Meyer Upper Extremity Motor Assessment, modified Ashworth scale, deep tendon reflexes, and muscle characteristics that included quantification of muscle stiffness, paresis and co-contraction during a voluntary reaching task and during passive movements. Surface electromyographic and myotonometric muscle stiffness data were obtained during movement trials. RESULTS: Biceps and triceps brachii muscle paresis and excess biceps brachii co-contraction during voluntary reaching had the highest correlations to decreased motor performance. Muscle tone measurements did not have significant correlations to upper extremity performance. CONCLUSION: Paresis of elbow flexors and extensors and excess co-contraction of the biceps brachii during voluntary reaching appear to be most predictive of upper extremity motor performance. Results are discussed in relation to the specific challenges these findings pose for spastic paresis clinical management.

Aged↗
PubMed2004

Roles of fascin in cell adhesion and motility.

Many cell interactions depend on the assembly of cell protrusions; these include cell attachment and migration in the extracellular matrix, cell-cell communication, and the ability of cells to sense their local environment. Cell protrusions are extensions of the plasma membrane that are supported internally by actin-based structures that impart mechanical stiffness. Fascin is a small, globular actin-bundling protein that has emerging roles in diverse forms of cell protrusions and in cytoplasmic actin bundles. The fascin-actin interaction is under complex regulation from the extracellular matrix, peptide factors and other actin-binding proteins. Recent developments advance our understanding of the multifaceted regulation of fascin and the roles of fascin-containing structures in cell adhesion, motility and invasion in the life of vertebrate organisms.

Actins↗
PubMed2001

Solution structure of hyaluronic acid oligomers by experimental and theoretical NMR, and molecular dynamics simulation.

The conformational properties of hyaluronic acid (HA) oligomers in aqueous solution were investigated by combining high-resolution NMR experimental results, theoretical simulation of NMR two-dimensional (2D) spectra by Complete Relaxation Matrix Analysis (CORMA), and molecular dynamics calculations. New experimental findings recorded for the tetra- and hexasaccharides enabled the stiffness of the HA and its viscoelastic properties to be interpreted. In particular, rotating frame nuclear Overhauser effect spectroscopy spectra provided new information about the arrangement of the glycosidic linkage. From (13)C NMR relaxation the rotational correlation time (tau(c)) were determined. The tau(c) were employed in the calculation of geometrical constraints, by using the MARDIGRAS algorithm. Restrained simulated annealing and 1 ns of unrestrained molecular dynamic simulations were performed on the hexasaccharide in a box of 1215 water molecules. The beta(1 --> 3) and beta(1 --> 4) glycosidic links were found to be rigid. The lack of rotational degree of freedom is due to direct and/or water-mediated interresidue hydrogen bonding. Both single or tandem water bridges were found between carboxylate group and N-acetil group. The carboxylate group of glucuronic acid is not involved in a direct link with the amide group of N-acetyl glucosamine and this facilitated bonding between the residue and the water molecules.

Biopolymers↗
PubMed1990

Collagen-collagen versus collagen-proteoglycan interactions in the determination of cartilage strength.

For articular cartilage to function as a stress-reducing layer in the joint, it must both deform to an appropriate level to achieve load-spreading as well as remain structurally coherent. Combined micromechanical and enzymatic studies of cartilage have demonstrated that the bulk of the extractable proteoglycans, while essential to the maintenance of compressive stiffness, contribute little to its cohesive strength. The study reported here clarifies fundamental aspects of the relationship between matrix components and the biomechanical function of cartilage.

Animals↗
PubMed2004

Screening for arthrofibrosis after anterior cruciate ligament reconstruction: analysis of association with human leukocyte antigen.

PURPOSE: Arthrofibrosis represents a severe complication of trauma and reconstructive joint surgery because of generalized connective tissue proliferation resulting in painful joint stiffness. It often appears stereotypical in terms of its clinical and pathologic features, comprising excess deposition of extracellular matrix proteins such as collagen type I, III, and VI and proliferation of fibroblasts. However, trauma and surgery around joints does not always lead to fibrosis, suggesting a genetic predisposition. For a number of autoimmune diseases, strong associations have been described. The objective of the study was to investigate whether an association of HLA (human leukocyte antigen) with primary arthrofibrosis exists. TYPE OF STUDY: Retrospective cohort study. METHODS: Seventeen patients with primary arthrofibrosis after autologous anterior cruciate ligament (ACL) reconstruction were identified and clinically reviewed. Blood samples were taken, and DNA was isolated by column extraction method. DNA samples were typed for the loci HLA-A, -B, -C, -DRB1, and -DQB1. Results were compared with the frequencies of allelic groups as determined for the caucasoid population. RESULTS: HLA-Cw*07 was significantly less often found in the patient group than in the general population (P =.022). The opposite effect was seen for Cw*08, which was found in 17.6% of the patient group but only in 3.8% of the reference group (P =.045). A significant difference was also seen for DQB1*06, because 23.5% of the patients but 48.6% of the reference group possessed an allelic variant of this group (P =.048). However, according to the relatively small number of patients, a statistical bias cannot be excluded. CONCLUSIONS: A possible link may exist between arthrofibrosis and HLA-Cw*07- and DQB1*06-negative as well as Cw*08-positive individuals. Further investigation is necesessary to confirm or vitiate the possible association. LEVEL OF EVIDENCE: Level IV.

Adult↗
PubMed2001

Hydroxyapatite as a filler for dental composite materials: mechanical properties and in vitro bioactivity of composites.

Hydroxyapatite (HAp) powder was treated with gamma-methacryloxypropyltrimethoxy-silane (gamma-MPS) using standard techniques in both non-polar and polar systems. Infrared spectra (DRIFT) and thermogravimetric analysis (TGA) confirmed the presence of gamma-MPS on the surface of the HAp filler particles. Series of experimental composites consisting of bisphenol-a-glycidyl methacrylate (BisGMA) based resin and untreated or treated HAp filler were produced to determine the mechanical properties and in vitro bioactivity. The incorporation of HAp filler into the BisGMA base resin had an enhancing effect on the flexural strength and Young's modulus of the base resin, the latter being increased by a factor of three. The mechanical properties of the filled resin were not affected by the surface treatment of the HAp, but filler loading was found to have a significant effect on Young's modulus. Higher proportions of silane-treated HAp of smaller particle size could be incorporated in the monomer phase giving rise to composites of higher stiffness. Examination of the fracture surfaces showed that the silanized HAp particles maintained better contact with the polymer matrix. In vitro study revealed that the composites incorporating silanized HAp formed a compact and continuous calcium phosphate layer on their surface after 4 weeks immersion in a simulated body fluid (SBF).

Journal Article↗
PubMed1995

Influence of graded changes in vasomotor tone on the carotid arterial mechanics in live spontaneously hypertensive rats.

1. The contribution of vasomotor tone to the increased stiffness of carotid arteries in living spontaneously hypertensive rats (SHR) is largely unknown. Whether a reduced vascular tone is associated with an increase or a decrease in arterial stiffness in vivo remains to be determined. The goal of the present investigation was to show that a decrease in vascular tone is associated with a decrease in arterial stiffness, independent of the structural composition of the arterial wall. 2. New high resolution echo-tracking techniques were used to evaluate pulsatile changes of carotid blood pressure and diameter following transient and graded changes of vasomotor tone produced by the dihydropyridine derivative, isradipine. Treatment for 8 weeks was given to groups of SHR rats either with a low (0.6 kg day-1) or a high (2.6 mg kg-1 day-1) dose. Another SHR group received an acute dose of 2.6 mg kg-1 day-1. Results were compared to those of placebo-treated Wystar-Kyoto (WKY) and SHR rats. Whatever the dosage, acute or chronic calcium blockade caused a decrease in blood pressure which was maximal 1 h after administration and disappeared after the 16th h. Carotid arterial thickness and the composition of the arterial wall was determined from histomorphometry. 3. In placebo-treated SHR, the inverse relationship relating blood pressure to carotid arterial distensibility was significantly shifted toward higher values of blood pressure compared to the curve of normotensive placebo-treated WKY rats. The curve of SHR receiving chronically a non antihypertensive (0.6 mg kg-1 day-1) isradipine dose prolonged that of placebo-treated SHR toward lower values of blood pressure, so that carotid distensibility was significantly higher than in WKY for the same diameter and blood pressure level (145 mmHg). With administration of a chronic antihypertensive dose (2.6 mg kg-1 day-1) causing a significant decrease in arterial function. Acute antihypertensive calcium blockade with a single isradipine dose (2.6 mg kg-1 day-1) caused a similar shift in the pressure-distensibility curve toward the WKY curve although the histomorphometric composition of the arterial wall differed significantly from that of chronically treated animals. 4. The study provides evidence that, in living SHR submitted to calcium blockade, (i) a low dose of isradipine causing no substantial antihypertensive effect is associated with a significant elevation of carotid arterial distensibility for the same pressure and diameter as normotensive controls, and (ii) an acute or chronic dose causing a substantial antihypertensive effect is associated with a transient shift of the SHR distensibility-pressure curve toward a physiological arterial function, increasing carotid distensibility for the same pressure and diameter as WKY controls. Since such findings were observed independently of the histomorphometric composition of the arterial wall, they imply that the transient decrease in arterial stiffness produced by calcium blockade should involve specific changes in the connections between arterial smooth muscle and extracellular matrix.

Animals↗
PubMed1992

Remodeling of the heart (membrane proteins and collagen) in hypertensive cardiopathy.

The basis for impaired left ventricular function of hearts in moderate to severe stages of hypertrophy and congestive heart failure remains uncertain. At the cellular level, the mechanisms governing the movements of calcium in the myocardium are actually depressed and might at least in part account for the slowing of the maximum shortening velocity and the impaired relaxation. These alterations of membrane proteins seem particularly important in species where the slowing of Vmax cannot be a consequence of the myosin heavy chain shift. They lead to an unstable equilibrium of calcium homeostasis and to calcium overload in heart failure. On the other hand, the enhanced density and remodeling of collagen in the hypertrophied heart, which would depend on elevation in circulating aldosterone, impair myocardial stiffness with diastolic dysfunction and lead to altered pumping capacity of the heart. Disturbances of calcium metabolism and matrix collagen remodeling enhance early afterdepolarizations and arrhythmias.

Animals↗
PubMed2000

Structure and mechanical properties of resistance arteries in hypertension: role of adhesion molecules and extracellular matrix determinants.

Abnormalities of resistance arteries may play a role in the pathogenesis and pathophysiology of hypertension in experimental animals and humans. Vessels that, when relaxed, measure <400 microm in lumen diameter act as the major site of vascular resistance and include a network of small arteries (lumen approximately 100 to 400 microm) and arterioles (<100 microm). Because increased peripheral resistance is generated by a narrowed lumen diameter, significant effort has been focused on determining the mechanisms that reduce lumen size. Three important vascular components are clearly involved, including alterations of vascular structure, mechanics (stiffness), and function. Structural abnormalities comprise a reduced lumen diameter and thickening of the vascular media, resulting in an increased media-lumen ratio. Changes in the mechanical properties of an artery, particularly increased stiffness, may also result in a reduced lumen diameter. These vascular abnormalities may be caused or influenced by the expression and/or topographic localization of extracellular matrix components, such as collagen and elastin, and by changes in cell-extracellular fibrillar attachment sites, such as adhesion molecules like integrins. This article discusses the abnormalities of resistance arteries in hypertension and reviews the evidence suggesting an important role for adhesive and extracellular matrix determinants.

Animals↗