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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This decade witnessed a resurgence of interest in vascular dementia (VaD) as an increasingly important cause of senile dementia. Although definitions of dementia in general, and of VaD in particular, are still controversial recent diagnostic criteria for VaD acknowledge that pathogenetic mechanisms different from multi-infarct dementia are important in dementia causation. These include subcortical strokes, mainly lacunes, global hypoxic-ischemic events during acute stroke, and ischemic periventricular white matter lesions of the Binswanger type. These lesions tend to be manifested primarily by alterations of frontal executive function control. The importance of these ischemic vascular lesions in the clinical expression of Alzheimer's disease (AD) in very old subjects has also been recognized. Clinically, VaD may present in two forms: Acute VaD includes large-vessel infarction, and lacunar dementia due to small-vessel disease, including thalamic and caudate strokes. Subacute VaD includes Binswanger's disease (BD), cerebral angiopathy with leukoencephalopathy and CADASIL. The discovery of CADASIL, a genetic form of VaD mapped to chromosome 19 as a mutation of the Notch 3 gene, opened research avenues into the pathogenesis of BD. Finally, epidemiological evidence suggests that it may be possible to prevent VaD--and perhaps degenerative senile dementia--by controlling hypertension and other vascular risk factors. These findings offer hope for prevention of this growing public health problem.
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PMID:Vascular dementia today. 1063 40

Clinical data and MRI findings are presented on 18 subjects from two families with neuropathologically confirmed CADASIL. DNA analysis revealed mutations in exon 4 of Notch 3 gene in both families. All family members with mutations in Notch 3 gene had extensive abnormalities on MRI, principally lesions in the white matter of the frontal lobes and in the external capsules. Of several family members in whom a diagnosis of CADASIL was suspected on the basis of minor symptoms, one had MRI changes consistent with CADASIL; none of these cases carried a mutation in the Notch 3 gene. MRI and clinical features that may alert the radiologist to the diagnosis of CADASIL are reviewed. However, a wide differential diagnosis exists for the MRI appearances of CADASIL, including multiple sclerosis and small-vessel disease secondary to hypertension. The definitive diagnosis cannot be made on MRI alone and requires additional evidence, where available, from a positive family history and by screening DNA for mutations of Notch 3 gene.
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PMID:Diagnosing CADASIL using MRI: evidence from families with known mutations of Notch 3 gene. 1087 67

Atypical phenotypes of CADASIL and corresponding anatomical data in two cases are described in 6 members of 2 new French families. In the first family, 4 cases in the same kindred were probably affected, two of them with a predominant psychiatric presentation, two others with dementia and a pseudo-bulbar syndrome of progressive evolution. No history of migraine or ischemic event were documented in any. In the propositus, the diagnosis was documented by skin biopsy, Notch 3 gene mutation and autopsy after the patient had died when 67 years old, 8 years after onset. Brain examination showed a widespread leukoencephalopathy with subcortical infarcts. Characteristic granular lesions of the small arteries of the brain and other organs were observed. In the second family, two cases are reported. One patient died when 63 years old after a subacute evolution mimicking intracranial hypertension. The anatomical diagnosis was retrospectively proven typical of CADASIL with Notch 3 immunostaining of arterial smooth muscle cells. The other case had a progressive evolution over 20 years of limb paresthesia with a mild spasticity diagnosed as a progressive form of multiple sclerosis. It was followed by a pseudo-bulbar syndrome and a mild subcortical dementia without acute ischemic attack. The diagnosis was confirmed by skin biopsy and mutation of the Notch 3 gene. This report illustrates
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PMID:[Atypical CADASIL phenotypes and pathological findings in two new French families]. 1145 85

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a hereditary arteriopathy caused by mutations of the Notch3 gene. The risk factors for cerebral microhaemorrhages (CM), their relationship to other MRI lesions in the disease and their potential clinical impact have not been previously defined. Our purpose was to examine the frequency, number and location of microhaemorrhages in a multicentre cohort study, defining predisposing factors and associated radiographic markers in CADASIL patients. We collected clinical data from 147 consecutive patients enrolled in an ongoing prospective cohort study. Degree of neurological disability and cognitive impairment were assessed by standardized scales. T(1)-weighted, FLAIR and T2*-weighted gradient-echo (GE) MRI sequences were performed. Volume and location of lacunar infarcts and white matter hyperintensity (WMH) were assessed. Number and location of CM were recorded. CM were present in 35% patients, most commonly occurring in the thalamus, brainstem and basal ganglia. The location of CM qualitatively differed from areas of lacunar infarction and WMH. There was a significant association between the presence of CM and a history of hypertension (P = 0.005), systolic blood pressure (SBP) (P = 0.014), haemoglobin A1c (HbA1c) (P = 0.004) and the volume of lacunar infarcts (P = 0.010) and WMHs (P = 0.046). The number of CM was independently associated with SBP (P = 0.005), the diagnosis of hypertension (P = 0.0004), volume of WMH (P = 0.0005) and lacunar infarcts (P = 0.004). In contrast, no association was found between blood pressure or HbA1c and the load of WMH or lacunar infarcts. The presence of CM was independently associated with increased modified Rankin scores. CM are independently associated with blood pressure and HbA1c as well as with lacunar infarct and WMH volume in CADASIL. Both the vascular risk factors and regional distribution of CM appear distinct from those associated with other MRI markers, suggesting a distinct pathological process. These lesions have a potential clinical impact in CADASIL. These findings further suggest that modulation of blood pressure and glucose levels might influence the course of the disease.
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PMID:Blood pressure and haemoglobin A1c are associated with microhaemorrhage in CADASIL: a two-centre cohort study. 1684 17

Ductal concretions in chronic pancreatitis (CP) are one of the causes of ductal obstruction, resulting in pancreatic ductal hypertension (PDH) and duct ectasia. Ductal epithelium subjected to chronic stress by PDH may undergo molecular alterations, thereby not only initiating and sustaining the inflammatory process but also activating molecules that have transforming potential. Acino-ductal metaplasia and pancreatic intraepithelial neoplasia (PanIN) are frequently seen in CP. Using laser capture microdissection, cDNA microarrays and Ingenuity Pathways Analysis, we found an altered Notch pathway in the ectatic ducts of CP. The microarray data was further validated by real-time PCR. We also found elevated transcripts of Notch receptors, Notch1 and Notch3 in microdissected ectatic ducts of CP. The Notch pathway ligands, Jagged/Delta-like and a Notch target, HES-related repressor protein (HERP), were up-regulated in ectatic compared to normal pancreatic ducts, while another target of Notch, hairy/enhancer of split (HES), was down-regulated. The transcripts of Delta-like1 and Jagged1 were increased 3.7-fold and 1.3-fold, respectively, while those of HERP1 were elevated 2.4-fold in the ectatic ducts of CP, compared to normal ducts. Immunohistochemistry showed that Jagged1 was not expressed in normal pancreatic ducts, while it was highly expressed in ectatic ducts. This pattern of Notch component alteration in ectatic ducts was mimicked to some extent in vitro in a human pancreatic duct epithelial (HPDE) cell line, when subjected to a pressure of 200 mmHg for 24 h. Therefore, we conclude that in the ectatic ducts of CP, PDH activates signalling pathways such as Notch, which have transforming potential.
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PMID:Evidence of Notch pathway activation in the ectatic ducts of chronic pancreatitis. 1806 60

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a systemic arterial disease characterized by impairment of vascular smooth muscle cell structure and function related to NOTCH3 mutations. Pathological findings include pathognomonic granular osmiophilic material (GOM) deposition with nonspecific hyalinization within the artery wall in a variety of tissues. The main clinical presentation is iterative strokes in young adults despite the lack of cardiovascular risk factors, leading to early dementia. Although arteriosclerosis and GOM have been found in kidneys from patients with CADASIL, kidney disease has been described only once up to now, in association with immunoglobulin A nephropathy. We report the case of a 61-year-old patient with a medical history of CADASIL and recent mild hypertension. His mother also showed neuropsychiatric symptoms and end-stage renal disease of unknown cause. The patient had a chronic kidney disease defined by means of estimated glomerular filtration rate using the 4-variable Modification of Diet in Renal Disease Study equation of 58 mL/min/1.73 m(2) associated with mild proteinuria and intermittent microscopic hematuria. Renal histological analysis showed severe arteriosclerosis and mild interstitial fibrosis. Glomeruli did not show mesangial immunoglobulin A deposition or focal segmental proliferation. Electron microscopic analysis showed typical GOM deposition in the vicinity of altered vascular smooth muscle cells in interlobular and juxtaglomerular arteries. The nephroangiosclerosis-like lesions were unusually severe in contrast to the recent mild hypertension. The presence of GOM strongly suggests that renal lesions were related to the NOTCH3 mutation. Here, we describe the first case of familial occurrence of kidney disease with decreased kidney function in the absence of coexisting nephropathy in patients with CADASIL. We discuss the role of NOTCH3 mutation in the pathogenesis of nephroangiosclerosis through functional impairment of renal microcirculation or primary Notch3-related vascular disease.
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PMID:Nephroangiosclerosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: is NOTCH3 mutation the common culprit? 1857 91

Notch receptor signaling is implicated in controlling smooth muscle cell proliferation and in maintaining smooth muscle cells in an undifferentiated state. Pulmonary arterial hypertension is characterized by excessive vascular resistance, smooth muscle cell proliferation in small pulmonary arteries, leading to elevation of pulmonary vascular resistance, right ventricular failure and death. Here we show that human pulmonary hypertension is characterized by overexpression of NOTCH3 in small pulmonary artery smooth muscle cells and that the severity of disease in humans and rodents correlates with the amount of NOTCH3 protein in the lung. We further show that mice with homozygous deletion of Notch3 do not develop pulmonary hypertension in response to hypoxic stimulation and that pulmonary hypertension can be successfully treated in mice by administration of N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a gamma-secretase inhibitor that blocks activation of Notch3 in smooth muscle cells. We show a mechanistic link from NOTCH3 receptor signaling through the Hairy and enhancer of Split-5 (HES-5) protein to smooth muscle cell proliferation and a shift to an undifferentiated smooth muscle cell phenotype. These results suggest that the NOTCH3-HES-5 signaling pathway is crucial for the development of pulmonary arterial hypertension and provide a target pathway for therapeutic intervention.
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PMID:Notch3 signaling promotes the development of pulmonary arterial hypertension. 1985

Proteins of the Notch receptor family are cell surface receptors that transduce signals between neighboring cells. The Notch signaling pathway is highly evolutionarily conserved and critical for cell fate determination during embryogenesis and early postnatal life, including many aspects of vascular development. The interaction of Notch receptor with its membrane-bound ligands leads to cleavage of the receptor into an intracellular domain that translocates to the nucleus and activates the transcription factor, C-promoter binding factor 1 (CBF1; also known as Recombination signal-binding protein for immunoglobulin kappa J region, RBPJ). To date, four Notch receptors have been characterized in humans. Of these, Notch3 is expressed only in arterial smooth muscle cells in the human. The functional importance of Notch3 signaling in human vascular smooth muscle cells has been recognized. Notch3 receptor signaling has been shown in several model systems to control vascular smooth muscle cell proliferation and maintain smooth muscle cells in an undifferentiated state. This review focuses on recent findings of the role of Notch3 in regulating vascular smooth muscle cell behavior and phenotype and discusses the potential role of Notch3 signaling in the genesis of pulmonary arterial hypertension.
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PMID:Notch signaling in pulmonary hypertension. 2020 37

Vascular cognitive impairment (VCI) encompasses vascular dementia and is the second most common cause of dementing illness after Alzheimer's disease. The main causes of VCI are: cerebral small vessel disease; multi-infarct dementia; strategic infarct (i.e. located in a functionally-critical brain area); haemorrhage/microbleed; angiopathy (including cerebral amyloid angiopathy); severe hypoperfusion (e.g. cardiac arrhythmia); and hereditary vasculopathy (e.g. cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CADASIL). In this systematic analysis, we aimed to relate cognitive and neuropathological features of experimental models to clinical VCI. We extracted data from 107 studies covering 16 models. These included: brief global ischaemic insults (in rats, mice or gerbils); chronic global hypoperfusion (rats, mice, gerbils); chronic hypertension (in primates or stroke-prone, spontaneously-hypertensive rats); multiple ischaemic lesions because of intra-vascular emboli (in rodents, rabbits or primates); strategic ischaemic lesions (in rats or mini-pigs); generalised vasculopathies, because of mutant Notch3, hyperhomocysteinaemia, experimental diabetes mellitus or lack of cerebral vasodilator M(5) receptors (rats or mice). Most cognitive testing showed deficits in working and reference memory. The lesions observed were microinfarcts, diffuse white matter lesions, hippocampal neuronal death, focal ischaemic lesions and micro-haemorrhages. The most-used model was bilateral carotid artery occlusion in rats, leading to chronic hypoperfusion and white matter injury.
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PMID:Experimental models of vascular dementia and vascular cognitive impairment: a systematic review. 2073 63

The Notch3 receptor participates in the development and maturation of vessels. Mutations of Notch3 in humans are associated with defective regulation of cerebral blood flow. To investigate the role of Notch3 in the regulation of renal hemodynamics, we used mice lacking expression of the Notch3 gene (Notch3-/- mice). Bolus injections of norepinephrine and angiotensin II increased renal vascular resistance and decreased renal blood flow in a dose-dependent manner in wild-type mice. In sharp contrast, renal vascular resistance of Notch3-/- mice varied little after boluses of norepinephrine and angiotensin II. Inversely, bradykinin and prostacyclin relaxed renal vasculature in wild-type mice. Both vasodilators had a negligible effect on renal vascular resistance of Notch3-/- mice. Afferent arterioles freshly isolated from Notch3-/- mice displayed decreased thickness of vascular wall compared with wild -type mice and showed a deficient contractile response to angiotensin II. To examine the physiopathological consequences of the above-described deficiency, hypertension was induced by continuous infusion of angiotensin II. Angiotensin II gradually increased blood pressure in both strains, but this increase was lesser in the Notch3-/- mice. Despite this blunted systemic effect, Notch3-/- mice displayed high mortality rates (65%) attributed to heart failure. In the kidney, the surviving Notch3-/- mice showed focal structural alterations characteristic of nephroangiosclerosis. These data show that Notch3 is necessary for the adaptive response of the renal vasculature to vasoactive systems. A deficiency in the expression of Notch3 could have important physiopathological consequences in the adaptation of the cardiac and renal function to chronic increase of blood pressure.
Hypertension 2011 Jun
PMID:Notch3 is essential for regulation of the renal vascular tone. 2151 68


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