elastin and Diabetic-Angiopathies

The microangiopathy under hyperglycemia and diabetes develops only in the microcirculation component of circulatory system. In this area considerable amount of pericytes is concentrated. These cells contain myofibrils and in circulatory mode envelop capillaries being situated on the outside of basilemma. It is possible that in a phylogenetic sense this is the earliest functional unity of endothelium monolayer as a pacemaker and pericytes as contractile elements which are the earliest "propeller" because of implementing the function of advancement of lymph, hemolymph and blood in capillaries. Probably, endothelium and pericytes formed the first variation of peristaltic "pump" for the purpose of blood advancement longwise of capillaries. Most probably, the state of distal part of arterial race (muscular type arterioles) impact the parameters of proximal part of arterial race (elastic type arterioles) and myocardium itself in the same extent as the state of "pump" in capillaries, endothelium and pericytes function impact the function of local peristaltic pumps (muscular type arterioles) in paracrine cenosis. It is supposed that the pericytes are the regulators of physical, hydraulic factor of activation of biologic reaction of transcitosis--excretion of nutrients and humoral mediators from capillaries to the pool of intercellular medium to perform the biologic function of homeostasis. Hyperglycemia, glycotoxins formation, bivalent substances (glyoxal, methilglyoxal, malonic dialdehyde) reacting simultaneously by both ends of molecule result in formation within collagen of areolar tissue of short transversal cross-links (glycosylation end product) which significantly increase rigidity (hardness) of capillary wall. In these conditions, myofibrils of pericytes no longer form directed deformation of capillary wall to effect peristalsis and advancement of hemolymph (blood later on) along capillaries according the synthesis of monolayer endothelium NO as a dilatation factor. This is the cause of blood circulation disturbance on the level of exchange capillaries and formation of chronic hypoxemia resulting in the only increase of rate of glycosylation chemical reaction. The microangiopathy is formed in the cells and tissues in an integrated pool of intercellular medium and never occurs in the cerebrospinal fluid pool where no hyperglycemia develops.

Topics: Arterioles; Capillaries; Cell Communication; Collagen; Diabetes Mellitus; Diabetic Angiopathies; Elastin; Extracellular Matrix; Glycation End Products, Advanced; Glycosylation; Humans; Hyperglycemia; Hypoxia; Pericytes

Arterial stiffness is an independent risk factor for premature cardiovascular morbidity and mortality that can be evaluated by noninvasive methods and can be reduced by good clinical management. The present chapter examines the association between arterial stiffness and cardiovascular risk factors including hypertension, metabolic syndrome, diabetes, advanced renal failure, hypercholesterolemia and obesity. The mechanisms responsible for the structural and functional modifications of the arterial wall are also described. We deal with parameters related to arterial compliance, focusing on two of them, pulse wave velocity and the augmentation index, useful in rapid assessment of arterial compliance by the bedside. Data that highlight the role of aortic pulse wave velocity and the augmentation index as independent factors in predicting fatal and nonfatal cardiovascular events in different populations are briefly presented. A number of lifestyle changes and traditional antihypertensive agents that improve arterial compliance are finally discussed. Novel therapies, such as statins, thiazolidindinediones, phosphodiesterase inhibitors and inhibitors or breakers of advanced glycation end product cross-links between colagen and elastin hold substantial promise.

Topics: Arteries; Blood Pressure; Cardiovascular Diseases; Diabetic Angiopathies; Elasticity; Elastin; Fibronectins; Humans; Hypertension; Matrix Metalloproteinases; Metabolic Syndrome; Obesity; Proteoglycans; Pulse

Diabetes affects the microcirculation, the large arteries and occasionally the large and small veins, by inducing vessel wall sclerosis. The degree of stiffening produced is linked to its duration. The ability of the diabetic's circulation to distribute blood is affected, especially during increased blood flow. In most tissues this causes no serious burden, but three tissues are unusually susceptible to disturbance--the retina, renal cortex, and peripheral nerve. They develop serious problems in many longstanding diabetics. Damage to the kidney appears to be linked to its unique combination of high blood flow rate and precise control of intraglomerular filtration pressure. As renal arteriolar intima hyalinizes, the glomerular mesangium increases in volume. Diabetic renal changes appear to become irreversible when a critical stage, manifested be albuminuria and hypertension, is reached. The resulting renal failure is associated with clumpy deposits of type IV collagen in the cortex, suggesting that local microvascular autoregulation has been lost. The retinal circulation forms late in fetal life in a process in which local oxygen tension controls new vessel formation. In adult diabetics, local retinal oxygenation is disrupted by a condition called capillary closure, and intraretinal microaneurysms form. In advanced retinopathy, new microvessel systems grow into the vitreous through defects in the internal limiting membrane, producing hemorrhage and vitreous opacification. Macular degeneration is also seen in older diabetics, suggesting that the choroidal circulation may also be compromised. Evidence for a microcirculatory role in diabetic peripheral nerve damage is not as conclusive as for the kidney and retina. The longest peripheral nerves are typically the most affected. Recent studies suggest that nerve damage can be produced by a disturbance in local pressure-flow relationships combined with epineurial mechanical constraint. Hypotheses about the pathogenesis of diabetic vascular sclerosis are reviewed, including collagen-stiffening, elastin degeneration, hemorheologic burden, metabolic disruption, increased permeability, and auto-immune disturbance.

Topics: Capillary Permeability; Chronic Disease; Collagen; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Neuropathies; Diabetic Retinopathy; Elastin; Glomerular Filtration Rate; Humans; Microcirculation; Regional Blood Flow; Renal Circulation; Retinal Vessels; Time Factors

Topics: Biomarkers; Case-Control Studies; Collagen Type IV; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Elastin; Enzyme-Linked Immunosorbent Assay; Female; Glycated Hemoglobin; Humans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Middle Aged; Risk Assessment

Proteins containing advanced glycation end products are highly immunogenic and anti-advanced glycation end products antibodies (anti-AGEs antibodies) are found in the sera of diabetics.. Enzyme-linked immunosorbent assay (ELISA) was used for measuring levels of anti-advanced glycation end products antibodies in sera of 93 patients with type 2 diabetes mellitus and arterial hypertension (mean age 61.4±11.3 years, diabetes duration 9.88±3.12 years; hypertension duration 9.28±4.98). These values were compared to serum anti-AGEs antibodies in 42 age and sex matched controls. Diabetics were divided in two groups according to presence or absence of microangiopathy, group 1 (n=67) and group 2 (n=26), respectively.. Serum levels of anti-AGEs antibodies in patients with type 2 diabetes mellitus and arterial hypertension were statistically significantly higher than those in the control group (1.39±0.39 vs. 1.05±0.32), (p<0.05). Group 1 showed significantly higher levels of anti-AGEs antibodies than those of healthy controls (1.53±0.14 vs. 1.05±0.32), (p<0.01). Anti-AGEs antibodies levels were higher in patients with microvascular complications than these in patients without complications. Anti-AGEs antibodies correlate with diastolic blood pressure (r=0.26, p=0.05) and body mass index (r=0.37, p=0.03). We found significantly higher percentage of positive patients for anti-AGEs antibodies (mean+2SD) in group 1 than in group 2.. Determining the levels of serum anti-AGEs antibodies can help physicians make early diagnosis and prognosis of the severity of late diabetic complications in hypertensive patients.

Topics: Aged; Albuminuria; Autoantibodies; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Neuropathies; Diabetic Retinopathy; Elastin; Female; Glycation End Products, Advanced; Humans; Hypertension; Male; Middle Aged

Vascular complications are associated with the progressive severity of diabetes, resulting in significant morbidity and mortality. This study quantifies functional vascular parameters and macrovascular structure in a rat model of type 1 diabetes. While there was no difference in the systemic arterial elastance (Ea) with 50 days of diabetes, changes were noted in the aorta and femoral artery including increased tunica media extracellular matrix content, decreased width of both the media and individual smooth muscle cell layers, and increased incidence of damaged mitochondria. Extracellular matrix proteins and elastin levels were significantly greater in the aorta of diabetic animals. These differences correlated with diminished matrix metalloprotease activity in the aorta of the diabetic animals. In conclusion, diabetes significantly altered the structure and ultrastructure of the aorta and femoral artery before systemic changes in arterial elastance could be detected.

Topics: Animals; Aorta; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Elastin; Extracellular Matrix; Extracellular Matrix Proteins; Femoral Artery; Male; Matrix Metalloproteinases; Mitochondria, Muscle; Muscle, Smooth, Vascular; Rats; Rats, Sprague-Dawley; Tunica Media; Vascular Resistance

Calcification and fibrosis reduce vascular compliance in arteriosclerosis. To better understand the role of osteopontin (OPN), a multifunctional protein upregulated in diabetic arteries, we evaluated contributions of OPN in male low-density lipoprotein receptor (LDLR)-/- mice fed a high-fat diet.. OPN had no impact on high-fat diet-induced hyperglycemia, dyslipidemia, or body composition. However, OPN-/-;LDLR-/- mice exhibited an altered time-course of aortic calcium accrual-reduced during initiation but increased with progression-versus OPN+/+;LDLR-/- controls. Collagen accumulation, chondroid metaplasia, and mural thickness were increased in aortas of OPN-/-;LDLR-/- mice. Aortic compliance was concomitantly reduced. Vascular reexpression of OPN (SM22-OPN transgene) reduced aortic Col2A1 and medial chondroid metaplasia but did not affect atherosclerotic calcification, Col1A1 expression, collagen accumulation, or arterial stiffness. Dosing with the proinflammatory OPN fragment SVVYGLR upregulated aortic Wnt and osteogenic gene expression, increased aortic β-catenin, and restored early-phase aortic calcification in OPN-/-;LDLR-/- mice.. OPN exerts stage-specific roles in arteriosclerosis in LDLR-/- mice. Actions phenocopied by the OPN metabolite SVVYGLR promote osteogenic calcification processes with disease initiation. OPN limits vascular chondroid metaplasia, endochondral mineralization, and collagen accumulation with progression. Complete deficiency yields a net increase in arteriosclerotic disease, reducing aortic compliance and conduit vessel function in LDLR-/- mice.

Topics: Amino Acid Sequence; Animals; Aorta; Arteriosclerosis; beta Catenin; Calcinosis; Calcium; Collagen; Diabetic Angiopathies; Elastin; Fibrosis; Male; Matrix Metalloproteinases; Mice; Mice, Knockout; Microfilament Proteins; Muscle Proteins; Osteopontin; Peptide Fragments; Promoter Regions, Genetic; Receptors, LDL; Signal Transduction; Vascular Resistance

An emerging body of evidence suggests that vascular remodeling in diabetic patients involves a perturbation of the balance between cell proliferation and cell death. Our aim was to study whether arteries and vascular smooth muscle cells (VSMCs) isolated from diabetic patients exhibit resistance to apoptosis induced by several stimuli. Internal mammary arteries (IMAs) were obtained from patients who had undergone coronary artery bypass graft surgery. Arteries from diabetic patients showed increasing levels of Bcl-2 expression in the media layer, measured by immunofluorescence and by Western blotting. Human IMA VSMCs from diabetic patients showed resistance to apoptosis, measured as DNA fragmentation and caspase-3 activation, induced by C-reactive protein (CRP) and other stimuli, such as hydrogen peroxide and 7beta-hydroxycholesterol. The diabetic cells also exhibited overexpression of Bcl-2. Knockdown of Bcl-2 expression with Bcl-2 siRNA in cells from diabetic patients reversed the resistance to induced apoptosis. Consistent with the above, we found that pretreatment of nondiabetic VSMCs with high glucose abolished the degradation of Bcl-2 induced by CRP. Moreover, cell proliferation was increased in diabetic compared with nondiabetic cells. This differential effect was potentiated by glucose. We conclude that the data provide strong evidence that arterial remodeling in diabetic patients results from a combination of decreased apoptosis and increased proliferation.

Topics: Aged; Apoptosis; Collagen; Coronary Vessels; Diabetic Angiopathies; Elastin; Female; Gene Expression Regulation; Glucose; Humans; Internal Mammary-Coronary Artery Anastomosis; Male; Mannitol; Middle Aged; Muscle, Smooth, Vascular; Proto-Oncogene Proteins c-bcl-2

Diabetes is a risk factor for the development of cardiovascular diseases associated with impaired angiogenesis or increased endothelial cell apoptosis.. Here it is shown that angiogenic repair of ischemic hindlimbs was impaired in Lepr(db/db) mice, a leptin receptor-deficient model of diabetes, compared with wild-type (WT) C57BL/6 mice, as evaluated by laser Doppler flow and capillary density analyses. To identify molecular targets associated with this disease process, hindlimb cDNA expression profiles were created from adductor muscle of Lepr(db/db) and WT mice before and after hindlimb ischemia using Affymetrix GeneChip Mouse Expression Set microarrays. The expression patterns of numerous angiogenesis-related proteins were altered in Lepr(db/db) versus WT mice after ischemic injury. These transcripts included neuropilin-1, vascular endothelial growth factor-A, placental growth factor, elastin, and matrix metalloproteinases implicated in blood vessel growth and maintenance of vessel wall integrity.. These data illustrate that impaired ischemia-induced neovascularization in type 2 diabetes is associated with the dysregulation of a complex angiogenesis-regulatory network.

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Elastin; Gene Expression Profiling; Hindlimb; Ischemia; Leptin; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microcirculation; Muscle, Skeletal; Neovascularization, Physiologic; Neuropilin-1; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; Transcription, Genetic

Antibodies to elastin breakdown products are found in the serum of all human subjects and correlate with their respective serum peptide levels. The presence of these antielastin antibodies (AEAbs) and the corresponding antigens in circulation leads to the formation of circulating immune complexes (CICs). The aim of this study was to determine if the serum levels of free AEAbs (not bound in CICs) correlate with the development of vascular complications in diabetic children. To this end, we used a method for detecting immune complexes (complement inhibition factor [CIF]-enzyme-linked immunosorbent assay [ELISA]) in combination with an ELISA for detection of AEAbs. The levels of free immunoglobulin G (IgG) AEAbs were studied in the sera of 54 diabetic children (mean age 12.3+/-4 years; diabetes duration 5.2+/-3.7 years). Thirty-two of the children had vascular complications (group 1), and 22 were without vascular complications (group 2). Twenty healthy children (mean age 13.6+/-4.2 years) were used as controls. The diabetics showed statistically significant higher levels of free AEAbs (0.490 E492+/-0.244 E492 vs 0.307 E492+/-0.081 E492; p = .02) compared with the control group. In group 1, free AEAbs showed statistically significant higher levels than controls (0.523+/-0.269 vs 0.307+/-0.081; p = .016). Eighteen of 54 (33%) patients were positive for free AEAbs (13 of 32 [41%] in group 1 and 5 of 22 [22%] in group 2). Free AEAb levels in all diabetics showed a correlation with systolic blood pressure (r = .44; p = .01), diastolic blood pressure (r = .46; p = .009), total cholesterol (r = .33; p = .05), triglycerides (r= .38; p = .03), high-density lipoprotein (r= -.46; p = .009), serum fructose (r= .43; p = .001), and microalbuminuria (r= .41; p = .002). Patients who had vascular pathology showed a correlation of free AEAbs with microalbuminuria (r= .434; p= .026), serum fructose (r= .63; p = .0004), hemoglobin A1c (r= .392; p = .043), and triglycerides (r= .456; p = .025). These findings suggest that elevated levels of free IgG AEAbs are associated with the development of diabetic vascular complications in children.

Topics: Adolescent; Autoantibodies; Case-Control Studies; Child; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Elastin; Female; Humans; Immunoglobulin G; Male

Levels of elastin-derived peptides (EDP) were determined by enzyme-linked immunosorbent assay (ELISA) in sera of 28 children with Type 1 (insulin-dependent) diabetes mellitus (mean age 11.6+/-2.8 years, diabetes duration 5.1+/-2.5 years). None of the children had clinical or laboratory evidence of vascular complications. The children were followed over a period of 6 years, and 24 healthy children of similar age and sex served as a control group. During the investigative period, 10 diabetic patients had increased EDP levels, with 9 having been diabetic for more than 5 years and 1 patient less than 5 years. Seven of these patients developed diabetic microvascular complications. In this group, EDP were independently associated with age (r=.39, P=.047), retinopathy (r=.48, P=.034), and antibodies to advanced glycation endproducts (AGE) (r=.52, P=.018). The data of this pilot study are not strong enough to appear that EDP are a useful predictor of subsequent development of microvascular complications. This may be due to the small number of subjects, short duration of the study, manner in which EDP or the endpoints were measured, or frequency of which EDP measurements were made. Further prospective and longer studies of larger populations are needed to identify the role of EDP as an early marker for the development of diabetic microvascular complications.

Topics: Adolescent; Child; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Elastin; Female; Humans; Longitudinal Studies; Male

Previous studies have shown that biomechanical analysis of aorta from diabetic subjects reveals a marked increase in stiffness compared to aorta from age-matched control subjects. In the present paper we have proposed that this increased stiffness can be attributed to glycation-induced inter-molecular cross-links based on a direct analysis of the two known glycation cross-links, the fluorescent pentosidine and the non-fluorescent NFC-1. There was a significant difference in the increase in concentration of both cross-links with increasing age for both the intima (p < 0.0025) and the media (p < 0.0005) from the diabetic compared to the control subjects, but no correlation with the mature enzymic cross-link hy droxylysyl-pyridinoline. Finally, we have obtained a significant correlation of stiffness with both glycation cross-links (NFC-1, r = 0.86; p < 0.005 and pentosidine r = 0.75, p < 0.05), but the concentration of NFC-1 is about 50 times greater than that of pentosidine, indicating that it is the major glycation cross-link responsible for the stiffening of the aorta.

Topics: Adult; Aged; Aging; Amino Acids; Aorta, Thoracic; Arginine; Collagen; Cross-Linking Reagents; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Elastin; Glycation End Products, Advanced; Humans; Lysine; Middle Aged; Time Factors

The relationship between glycation of the aortic elastin and calcium deposits in the aorta was studied in streptozocin (STZ)-induced diabetic rats. 5-Hydroxymethylfurfural (5-HMF) which was released from aortic elastin by acid, was assayed after STZ treatment as an index of early stage glycation. The amount of released 5-HMF increased at 5 weeks and paradoxically decreased at 10 weeks after STZ treatment, though it remained higher than that of control rats. This paradoxical pattern was reproduced by the in vitro incubation of elastin with glucose and it is presumably due to further advancement of glycation reactions in diabetic rats. The level of 5-HMF did not change significantly in control rats at corresponding time points of 9, 11 and 16 weeks of age. Fluorescence of porcine pancreatic elastase I-digested elastin which served as an index of advanced glycation, increased by 1.6 times at 3 weeks and reached a maximum of 1.9-fold higher than that of control rats at 10 weeks. The calcium content of the aorta at 10 weeks in diabetic rats was significantly increased by 1.4-fold compared with control rats. This study showed that the increased elastin glycation in the aorta even at the early stage of diabetes is associated with calcium deposit in the aorta. These results are consistent with the interpretation that elastin glycation in the aorta is the potential accelerating factor for diabetic macroangiopathy.

Topics: Animals; Aorta; Blood Glucose; Body Weight; Calcium; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Elastin; Glycated Hemoglobin; Glycosylation; Male; Rats; Rats, Wistar

Topics: Adult; Aged; Aged, 80 and over; Arteriosclerosis; Collagen; Diabetic Angiopathies; Elastin; Glycosaminoglycans; Humans; Male; Middle Aged

Healthy subjects aged between 25 and 60 (20 cases) and between 61 and 65 (5 cases), and diabetic patients with vascular damage, aged between 24 and 62 (6 cases), were tested by a new method for the detection and identification of elastin-antielastin circulating immune complexes (CIC) in human sera. Such immune complexes were found in all patients' sera and only in one of the controls (at the age of 65). Among different patients, the elastin-antielastin CIC varied in size and elastin content, showing some correlation between these two characteristics and the existence of microvascular complications, as proved by the clinical and paraclinical investigation of the patients.

Topics: Adult; Antigen-Antibody Complex; Diabetes Complications; Diabetic Angiopathies; Elastin; Humans; Middle Aged; Vascular Diseases

Topics: Aorta; Arteriosclerosis; Collagen; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Elastin; Humans

Histochemical investigations on elastic membranes of vessels under normally and diabetic conditions have been accomplished. These studies were made on man (diabetic and non-diabetic subjects) and on rats with streptozotocin-diabetes. The results are comparable among one another. The amino acids histidine, tyrosine and tryptophan were not demonstrable. The detection of primary NH2-groups (ninhydrin-Schiff-method and o-diacetylbenzen-reaction) was positive however. The results of the reactions in healthy men and animals were more distinct than in diabetic human subjects and animals. In healthy children the intensities of the histochemically reactions were higher than in adults.

Topics: Adult; Age Factors; Amino Acids; Animals; Arteries; Child; Diabetes Mellitus; Diabetic Angiopathies; Elastic Tissue; Elastin; Histidine; Histocytochemistry; Humans; Rats; Streptozocin; Tryptophan; Tyrosine

Topics: Animals; Aorta; Aorta, Abdominal; Aorta, Thoracic; Chondroitin; Collagen; Diabetic Angiopathies; DNA; Dogs; Elastin; Glycosaminoglycans; Growth Hormone; Heparin; Hyaluronic Acid; Hypophysectomy