Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study focuses on the differential response of three branch levels of the mesenteric resistance arterial vasculature of 450-gram Sprague-Dawley rats infused continuously with angiotensin II (A-II) for 4, 7 and 14 days at a rate of 435 ng/kg/min, with an associated period of hypertension. The three branch levels (types I, II and III) were characterized by light microscopy and immunostaining using monoclonal antibodies for proliferating cell nuclear antigen, ED-1 (specific for rat monocytes/macrophages) and alpha smooth muscle cell (SMC) actin. Cross-sectional areas of the vascular walls were determined morphometrically. In situ hybridizations were performed on paraffin sections using both sense and antisense 35S-labeled cRNA probes generated from rat SMC osteopontin and elastin cDNAs. In the type-I (penetrating) arteries from A-II-infused animals, there was massive fibrinoid necrosis, a marked fibroproliferative perivascular response, intense monocyte/macrophage infiltration, striking SMC osteopontin and elastin gene expression; SMC, fibroblast and monocyte/macrophage DNA synthesis; and significant increase in the cross-sectional areas of the vascular walls. In the same animals, DNA synthesis also occurred in the larger mesenteric arteries of types II and III where it is associated with significant enlargement of the walls by SMC hypertrophy but without overt morphologic damage. It is suggested that the monocyte/macrophage infiltration and fibroproliferative response of type-I arteries may be related to A-II-induced osteopontin gene expression. Angiotensin infusion in the rat may represent a reproducible model of microvascular injury that can be utilized to elucidate the cellular and molecular biology of a variety of disease states such as hypertension and diabetes mellitus.
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PMID:Immunohistochemical and molecular characterization of the differential response of the rat mesenteric microvasculature to angiotensin-II infusion. 892 18

Evolution of species has led to the appearance of circulatory systems including blood vessels and one or more pulsatile pumps, typically resulting in a low-pressurised open circulation in most invertebrates and a high-pressurised closed circulation in vertebrates. In both open and closed circulations, the large elastic arteries proximal to the heart damp out the pulsatile flow and blood pressure delivered by the heart, in order to limit distal shear stress and to allow regular irrigation of downstream organs. To achieve this goal, networks of resilient and stiff proteins adapted to each situation--i.e. low or high blood pressure--have been developed in the arterial wall to provide it with non-linear elasticity. In the low-pressurised circulation of some invertebrates, the mechanical properties of arteries can almost be entirely microfibril-based, whereas, in high-pressurised circulations, they are due to an interplay between a highly resilient protein, an elastomer in the octopus and elastin in most vertebrates, and the rather stiff protein collagen. In vertebrate development, elastin is incorporated in elastic fibres, on a earlier deposited scaffold of microfibrils. The elastic fibres are then arranged in functional concentric elastic lamellae and, with the smooth muscle cells, lamellar units. The microfibrils may also play a direct functional role in all mature arteries of high- and low-pressurised circulations. Finally, since blood pressure regularly increases with developmental stages, it appears possible that the early deposition of microfibrils, which are highly-conserved in evolution, corresponds, at least in part, to an early microfibril-driven elasticity in low-pressurised arteries, present across species. In vertebrates, when pressure developmentally rises above a threshold value, the vascular wall stress may turn on the expression of other resilient protein genes, including the elastin gene. Elastin would then be deposited on microfibrils and resulting in the elastic fibre network and elastic lamellae whose mechanical properties are adapted to allow for proper arterial work at higher pressures.
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PMID:Function-structure relationship of elastic arteries in evolution: from microfibrils to elastin and elastic fibres. 1142 67

We report the case of a 7-year-old male child diagnosed with Williams-Beuren syndrome and arterial hypertension refractory to clinical treatment. The diagnosis was confirmed by genetic study. Narrowing of the descending aorta and stenosis of the renal arteries were also diagnosed. Systemic vascular alterations caused by deletion of the elastin gene may occur early in individuals with Williams-Beuren syndrome, leading to the clinical manifestation of systemic arterial hypertension refractory to drug treatment.
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PMID:Arterial hypertension in a child with Williams-Beuren syndrome (7q11.23 chromosomal deletion). 1221 91

Extracellular matrix molecules such as elastin and collagens provide mechanical support to the vessel wall. In addition to its structural role, elastin is a regulator that maintains homeostasis through biologic signaling. Genetically determined minor modifications in elastin and collagen in the aorta could influence the onset and evolution of arterial pathology, such as hypertension and its complications. We previously demonstrated that the inbred Brown Norway (BN) rat shows an aortic elastin deficit in both abdominal and thoracic segments, partly because of a decrease in tropoelastin synthesis when compared with the LOU rat, that elastin gene polymorphisms in these strains do not significantly account for. After a genome-wide search for quantitative trait loci (QTL) influencing the aortic elastin, collagen, and cell protein contents in an F2 population derived from BN and LOU rats, we identified on chromosomes 2 and 14, 3 QTL specifically controlling elastin levels, and a further highly significant QTL on chromosome 17 linked to the level of cell proteins. We also mapped 3 highly significant QTL linked to body weight (on chromosomes 1 and 3) and heart weight (on chromosome 1) in the cross. This study demonstrates the polygenic control of the content of key components of the arterial wall. Such information represents a first step in understanding possible mechanisms involved in dysregulation of these parameters in arterial pathology.
Hypertension 2005 Mar
PMID:Chromosomal mapping of quantitative trait loci controlling elastin content in rat aorta. 1566 57

Supravalvular aortic stenosis (SVAS) is associated with decreased elastin and altered arterial mechanics. Mice with a single deletion in the elastin gene (ELN(+/-)) are models for SVAS. Previous studies have shown that elastin haploinsufficiency in these mice causes hypertension, decreased arterial compliance, and changes in arterial wall structure. Despite these differences, ELN(+/-) mice have a normal life span, suggesting that the arteries remodel and adapt to the decreased amount of elastin. To test this hypothesis, we performed in vitro mechanical tests on abdominal aorta, ascending aorta, and left common carotid artery from ELN(+/-) and wild-type (C57BL/6J) mice. We compared the circumferential and longitudinal stress-stretch relationships and residual strains. The circumferential stress-stretch relationship is similar between genotypes and changes <3% with longitudinal stretch at lengths within 10% of the in vivo value. At mean arterial pressure, the circumferential stress in the ascending aorta is higher in ELN(+/-) than in wild type. Although arterial pressures are higher, the increased number of elastic lamellae in ELN(+/-) arteries results in similar tension/lamellae compared with wild type. The longitudinal stress-stretch relationship is similar between genotypes for most arteries. Compared with wild type, the in vivo longitudinal stretch is lower in ELN(+/-) abdominal and carotid arteries and the circumferential residual strain is higher in ELN(+/-) ascending aorta. The increased circumferential residual strain brings the transmural strain distribution in ELN(+/-) ascending aorta close to wild-type values. The mechanical behavior of ELN(+/-) arteries is likely due to the reduced elastin content combined with adaptive remodeling during vascular development.
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PMID:Effects of elastin haploinsufficiency on the mechanical behavior of mouse arteries. 1586 65

Williams-Beuren syndrome (WBS), caused by a heterozygous deletion at 7q11.23, represents a model for studying hypertension, the leading risk factor for mortality worldwide, in a genetically determined disorder. Haploinsufficiency at the elastin gene is known to lead to the vascular stenoses in WBS and is also thought to predispose to hypertension, present in approximately 50% of patients. Detailed clinical and molecular characterization of 96 patients with WBS was performed to explore clinical-molecular correlations. Deletion breakpoints were precisely defined and were found to result in variability at two genes, NCF1 and GTF2IRD2. Hypertension was significantly less prevalent in patients with WBS who had the deletion that included NCF1 (P=.02), a gene coding for the p47(phox) subunit of the NADPH oxidase. Decreased p47(phox) protein levels, decreased superoxide anion production, and lower protein nitrotyrosination were all observed in cell lines from patients hemizygous at NCF1. Our results indicate that the loss of a functional copy of NCF1 protects a proportion of patients with WBS against hypertension, likely through a lifelong reduced angiotensin II-mediated oxidative stress. Therefore, antioxidant therapy that reduces NADPH oxidase activity might have a potential benefit in identifiable patients with WBS in whom serious complications related to hypertension have been reported, as well as in forms of essential hypertension mediated by a similar pathogenic mechanism.
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PMID:Hemizygosity at the NCF1 gene in patients with Williams-Beuren syndrome decreases their risk of hypertension. 1653 85

Mice heterozygous for the elastin gene (ELN(+/-)) show unique cardiovascular properties, including increased blood pressure and smaller, thinner arteries with an increased number of lamellar units. Some of these properties are also observed in humans with supravalvular aortic stenosis, a disease caused by functional heterozygosity of the elastin gene. The arterial geometry in ELN(+/-) mice is contrary to the increased thickness that would be expected in an animal demonstrating hypertensive remodeling. To determine whether this is due to a decreased capability for cardiovascular remodeling or to a novel adaptation of the ELN(+/-) cardiovascular system, we increased blood pressure in adult ELN(+/+) and ELN(+/-) mice using the two-kidney, one-clip Goldblatt model of hypertension. Successfully clipped mice have a systolic pressure increase of at least 15 mmHg over sham-operated animals. ELN(+/+) and ELN(+/-)-clipped mice show significant increases over sham-operated mice in cardiac weight, arterial thickness, and arterial cross-sectional area with no changes in lamellar number. There are no significant differences in most mechanical properties with clipping in either genotype. These results indicate that ELN(+/+) and ELN(+/-) hearts and arteries remodel similarly in response to adult induced hypertension. Therefore, the cardiovascular properties of ELN(+/-) mice are likely due to developmental remodeling in response to altered hemodynamics and reduced elastin levels.
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PMID:Elastin-insufficient mice show normal cardiovascular remodeling in 2K1C hypertension despite higher baseline pressure and unique cardiovascular architecture. 1740 Jul 10

Diseases linked to the elastin gene arise from loss-of-function mutations leading to protein insufficiency (supravalvular aortic stenosis) or from missense mutations that alter the properties of the elastin protein (dominant cutis laxa). Modeling these diseases in mice is problematic because of structural differences between the human and mouse genes. To address this problem, we developed a humanized elastin mouse with elastin production being controlled by the human elastin gene in a bacterial artificial chromosome. The temporal and spatial expression pattern of the human transgene mirrors the endogenous murine gene, and the human gene accurately recapitulates the alternative-splicing pattern found in humans. Human elastin protein interacts with mouse elastin to form functional elastic fibers and when expressed in the elastin haploinsufficient background reverses the hypertension and cardiovascular changes associated with that phenotype. Elastin from the human transgene also rescues the perinatal lethality associated with the null phenotype. The results of this study confirm that reestablishing normal elastin levels is a logical objective for treating diseases of elastin insufficiency such as supravalvular aortic stenosis. This study also illustrates how differences in gene structure and alternative splicing present unique problems for modeling human diseases in mice.
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PMID:Functional rescue of elastin insufficiency in mice by the human elastin gene: implications for mouse models of human disease. 1776 33

Williams-Beuren syndrome (WBS) is a microdeletion disorder caused by heterozygous loss of approximately 1.5-Mb pairs of DNA from chromosome 7. Patients with WBS have a characteristic constellation of medical and cognitive findings, with a hallmark feature of generalized arteriopathy presenting as stenoses of elastic arteries and hypertension. Human and mouse studies establish that defects in the elastin gene, leading to elastin haploinsufficiency, underlie the arteriopathy. In this review we describe potential links between elastin expression and arteriopathy, possible explanations for disease variability, and current treatment options and their limitations, and we propose several new directions for the development of nonsurgical preventative therapies based on insights from elastin biology.
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PMID:Mechanisms and treatment of cardiovascular disease in Williams-Beuren syndrome. 1845 1

Williams-Beuren syndrome (WBS) (OMIM# 194050) is a rare, most often sporadic, genetic disease caused by a chromosomal microdeletion at locus 7q11.23 involving 28 genes. Among these, the elastin gene codes for the essential component of the arterial extracellular matrix. Developmental disorders usually associate an atypical face, cardiovascular malformations (most often supravalvular aortic stenosis and/or pulmonary artery stenosis) and a unique neuropsychological profile. This profile is defined by moderate mental retardation, relatively well-preserved language skills, visuospatial deficits and hypersociability. Other less known or rarer features, such as neonatal hypercalcemia, nutrition problems in infancy, ophthalmological anomalies, hypothyroidism, growth retardation, joint disturbances, dental anomalies and hypertension arising in adolescence or adulthood, should be treated. The aim of this paper is to summarize the major points of WBS regarding: (i) the different genes involved in the deletion and their function, especially the elastin gene and recent reports of rare forms of partial WBS or of an opposite syndrome stemming from a microduplication of the 7q11.23 locus, (ii) the clinical features in children and adults with a focus on cardiovascular injury, and (iii) the specific neuropsychological profile of people with WBS through its characteristics, the brain structures involved, and learning.
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PMID:[Williams-Beuren syndrome: a multidisciplinary approach]. 1909 73


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