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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The present study was conducted to analyse the release and production of mitogen in cultured aortic endothelial cells of stroke-prone spontaneously hypertensive rats (SHRSP), for the further understanding of the role of arterial endothelial cells in the genesis of vascular lesions in hypertension. 2. The cultured aortic endothelial cells derived from SHRSP increased released mitogens were compared with those from control Wistar-Kyoto rats (WKY) with respect to cultured vascular medial smooth muscle cells and fibroblasts. 3. Biochemical analyses determined that the major part of mitogen released from aortic endothelial cells of both SHRSP and controls was the platelet-derived growth factor B-chain. 4. Further northern analyses revealed that the transcripts of PDGF B-chain were constitutively accumulated three- to four-fold in quiescent aortic endothelial cells from SHRSP, compared with those from WKY through passages 2 to 5. 5. However, the half-lives of the transcripts after actinomycin D treatment were 1.12 h (s.d. = 0.14, n = 4) and 1.28 h (s.d. = 0.08, n = 3), in SHRSP and in WKY, respectively, showing no significant difference. 6. These suggest that the increased accumulated transcripts of PDGF B-chain in SHRSP are due to an enhanced transcriptional rate. These enhanced release and production of PDGF-B chain in arterial endothelial cells, which may be induced under chronic hypertensive conditions, is suggested to contribute to the genesis of vascular lesion in hypertension, through the stimulation of vascular smooth muscle cell proliferation and hypertrophy.
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PMID:Platelet-derived growth factor B-chain comprises the major part of enhanced released mitogen from aortic endothelial cells of stroke-prone spontaneously hypertensive rats. 907 22

The combination therapy with ACE inhibitors, angiotensin II type 1 (AT(1)) receptor antagonists, or calcium channel antagonists may exert more beneficial effects on cardiovascular diseases than monotherapy. Perindopril, candesartan cilexetil, or amlodipine alone or the combination of low doses of each agent was administered orally to stroke-prone spontaneously hypertensive rats (SHRSP) for 4 weeks to compare the hypotensive or cardiovascular effects. Although perindopril (2 mg/kg), candesartan cilexetil (2 mg/kg), or amlodipine (3 mg/kg) alone caused comparable hypotensive effects in SHRSP, monotherapy with perindopril or candesartan decreased left ventricular (LV) weight; mRNA levels for atrial natriuretic factor, skeletal alpha-actin, and collagen types I and III; and aortic weight and platelet-derived growth factor-beta receptor tyrosine phosphorylation to a greater extent than monotherapy with amlodipine. Although monotherapy with a low dose (0.2 mg/kg) of perindopril or candesartan cilexetil did not significantly reduce the LV mRNA levels and aortic platelet-derived growth factor-beta receptor phosphorylation of the SHRSP, combination therapy at such a low dose normalized these parameters more potently than the use of amlodipine (3 mg/kg) alone. Although perindopril or candesartan cilexetil alone at 0.05 mg/kg did not decrease the blood pressure of the SHRSP, such a low dose of combination therapy decreased LV weight and atrial natriuretic factor mRNA levels of the SHRSP to a greater extent than amlodipine alone or amlodipine combined with perindopril or candesartan cilexetil. Our results provide evidence that suggests the combination of an ACE inhibitor and an AT(1) receptor antagonist may be more effective in the treatment of cardiac and vascular diseases than the combination of a calcium channel blocker with an ACE inhibitor or an AT(1) receptor antagonist or monotherapy with each agent.
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PMID:Cardiovascular effects of combination of perindopril, candesartan, and amlodipine in hypertensive rats. 1072 May 93

It is unclear whether the previous in vitro evidence of a link between angiotensin II (Ang II) and growth factor receptors can apply to the in vivo situation. In this study, we examined vascular platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) receptor activation in stroke-prone spontaneously hypertensive rats (SHRSP) and the role of Ang II. Tyrosyl phosphorylation of the growth factor receptors was determined by Western blot analysis coupled with immunoprecipitation. Tyrosyl phosphorylation of the aortic PDGF beta-receptor, but not the EGF receptor, was chronically increased in SHRSP with hypertension, compared with normotensive rats, being accompanied by increased extracellular signal-regulated kinase (ERK) activity. Treatment of SHRSP with ACE inhibitors (perindopril or enalapril) significantly reduced aortic PDGF beta-receptor tyrosyl phosphorylation and ERK activity, whereas treatment with hydralazine failed to reduce these activities. Therefore, these aortic changes in SHRSP were mediated by Ang II in response to vascular ACE. Ang II was infused into rats to examine the effects on aortic growth factor receptors. Chronic Ang II infusion, via the angiotensin type 1 receptor, significantly increased activation of the aortic PDGF beta-receptor but not the EGF receptor. Thus, the aortic PDGF beta-receptor, activated by ACE-mediated Ang II, seems to be responsible for vascular remodeling in hypertensive rats.
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PMID:In vivo activation of rat aortic platelet-derived growth factor and epidermal growth factor receptors by angiotensin II and hypertension. 1111 50

Recent studies have reported that estrogen replacement therapy (ERT) reduces the risk of cardiovascular diseases in postmenopausal women. However, mechanisms responsible for this effect are not yet completely understood, and ERT is associated with carcinogenic side effects in women and feminizing effects in men. Because soybean isoflavones, a group of natural phytoestrogens, have only weak estrogenic activity and are not known to have side effects such as carcinogenesis and feminization, we evaluated the effects of genistein, daidzein and glycitein on the growth and DNA synthesis of aortic smooth muscle cells (SMC) from stroke-prone spontaneously hypertensive rats (SHRSP). SMC were cultured in dishes and proliferated on 10% dextran-coated charcoal/fetal bovine serum, and then treated with 0.1-30 micromol/L of genistein, daidzein or glycitein to investigate cell proliferation (cell number) and DNA synthesis (cell proliferation ELISA system), respectively. We also studied their effects on platelet-derived growth factor (PDGF)-BB (20 microg/L)-induced SMC proliferation. Soybean isoflavones inhibited proliferation and DNA synthesis of SMC from SHRSP in a concentration-dependent manner. Inhibition was significant at 3 micromol/L of genistein and 10 micromol/L of both daidzein and glycitein. For significant inhibition of PDGF-BB-induced SMC proliferation, concentrations as low as 0.1 micromol/L of each isoflavone were effective. These isoflavones, with their inhibitory effects on natural and PDGF-BB-induced SMC proliferation, may be useful in attenuatating such proliferation, a basic mechanism involved in atherosclerotic vascular change, thereby preventing atherosclerotic cardiovascular diseases.
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PMID:Genistein, daidzein and glycitein inhibit growth and DNA synthesis of aortic smooth muscle cells from stroke-prone spontaneously hypertensive rats. 1128 18

We examined the effects of the platelet-derived growth factor (PDGF) A-chain antisense oligodeoxynucleotides (ODN) on cardiovascular organ growth in stroke-prone spontaneously hypertensive rats (SHR-SP) in vivo. Expression of PDGF A-chain mRNA was higher in the aorta and kidney in 9-week-old SHR-SP than in Wistar-Kyoto (WKY) rats. A phosphorothioate-linked 15-mer antisense ODN complementary to the initiation codon region of rat PDGF A-chain mRNA and a control sense ODN were infused subcutaneously into SHR-SP/Izumo at a dose of 90 ng/g body weight/day for 28 days using an implanted ALZET pump. The PDGF A-chain antisense ODN did not affect blood pressure or body weight. The antisense ODN significantly inhibited [3H]thymidine incorporation into the DNA in the aorta and kidney but not in the heart. Infusion of the antisense ODN considerably reduced production of PDGF A-chain protein but did not affect expression of PDGF A-chain mRNA. Infusion of the antisense ODN considerably improved the arterial and renal tissue damage in SHR-SP morphologically. From these findings, it can be confirmed that suppression of PDGF A-chain by the antisense DNA is useful as a gene therapy for treating cardiovascular organ damage in hypertension.
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PMID:Effects of PDGF A-chain antisense oligodeoxynucleotides on growth of cardiovascular organs in stroke-prone spontaneously hypertensive rats. 1136 65

The Notch family of receptors and downstream effectors plays a critical role in cell fate determination during vascular ontogeny. Moreover, the human cerebral autosomal dominant artriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome of premature stroke and dementia is a heritable arteriopathy with alterations in vascular smooth muscle cells (VSMCs) resulting from mutations within Notch3. However, the expression and regulation of the Notch and hairy-related transcription factor (HRT) pathway in adult VSMCs in vitro and in vivo remain poorly characterized. The present study documents that the well-described modulation of VSMC fate in response to vascular injury and growth factor activation involves a coordinate regulation of the Notch and HRT pathways. Furthermore, platelet-derived growth factor promotes a similar coordinate down-regulation of the Notch receptors and HRT genes in cultured VSMCs via an ERK-dependent signaling pathway. Moreover, we established that HRT1 and HRT2 are direct downstream target genes of Notch3 signaling in VSMCs and determined that the activity of the nuclear protein RBP-Jk is essential for their regulation. These findings provide initial insight into the context- and cell type-dependent coordinate regulation of Notch3 and downstream HRT transcriptional pathway effector genes in VSMCs in vitro and in vivo that may have important implications for understanding the role of Notch signaling in human health and vascular disease.
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PMID:Coordinate Notch3-hairy-related transcription factor pathway regulation in response to arterial injury. Mediator role of platelet-derived growth factor and ERK. 1197 2

The molecular mechanism of glomerular injury in hypertension remains to be clarified. In this study, to examine the possible role of platelet-derived growth factor (PDGF) receptors in hypertensive glomerular injury, we specifically measured glomerular PDGF receptor tyrosine phosphorylation in various models of hypertensive rats using immunoprecipitation and Western blot analysis. A high-salt diet significantly enhanced glomerular PDGF beta-receptor tyrosine phosphorylation of Dahl-salt sensitive rats (DS-rats) without an increase in its protein levels, and this enhancement was associated with an elevation of blood pressure and glomerular injury. Stroke-prone spontaneously hypertensive rats (SHRSP) at hypertensive phase also had higher glomerular PDGF beta-receptor tyrosine phosphorylation levels than control Wistar-Kyoto rats (WKY), while SHR did not. Thus, DS-rats and SHRSP, which are well known to represent severe glomerular injury, had the enhanced PDGF beta-receptor tyrosine phosphorylation, while SHR, a hypertensive model without significant glomerular injury had no increased tyrosine phosphorylation. Treatment of DS-rats or SHRSP with benidipine, a calcium channel blocker, significantly lessened the increase in glomerular PDGF beta-receptor tyrosine phosphorylation, reduction of urinary protein and albumin excretion. These results suggest that the enhanced activation of glomerular PDGF beta-receptors may be responsible for the development of hypertensive glomerular injury and that the suppression of this receptor activation by a calcium channel blocker may contribute to its renal protective effects.
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PMID:Enhancement of glomerular platelet-derived growth factor beta-receptor tyrosine phosphorylation in hypertensive rats and its inhibition by calcium channel blocker. 1204 46

Fetal rat kidney cells produce high levels of glial-derived neurotrophic factor (GDNF) and exert neuroprotective effects when transplanted into the brain in animal models of Parkinson's disease and stroke. The purpose of the present experiment was to produce kidney cell lines that secrete GDNF. Genes encoding two truncated N-terminal fragments of SV40 large T antigen, T155g and T155c, which does not code for small t antigen, were used. T155g was transduced into E17 cultured fetal Sprague-Dawley rat kidney cortex cells using a plasmid vector, and T155c was transduced with a plasmid and a retroviral vector. Sixteen clones were isolated from cultures transfected with the T155g-expressing plasmid. No cell lines were obtained with T155c. Four clones produced GDNF at physiological concentrations ranging from 55 to 93 pg/ml of medium. These four clones were transplanted into the ischemic core or penumbra of rats that had undergone middle cerebral artery occlusion (MCAO). Three of the four clones reduced the volume of infarction and the behavioral abnormalities normally resulting from MCAO. Blocking experiments with antibodies to GDNF and platelet-derived growth factor (PDGF) suggested that these growth factors contributed only minimally to the reduction in infarct volume and behavioral abnormality. These cell lines may be useful for intracerebral transplantation in animal models of brain injury, stroke, or Parkinson's disease.
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PMID:T155g-immortalized kidney cells produce growth factors and reduce sequelae of cerebral ischemia. 1207 90

Mutations in the human Notch 3 gene cause the vascular stroke and dementia syndrome CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) characterized by degeneration of vascular smooth muscle cells and multiple small infarcts in the white and deep gray matter of the brain. Here we have analyzed the expression pattern of the Notch 3 gene in the pre- and postnatal mouse brain. Prenatal Notch 3 expression is restricted to a scattered population of cells within the vessel wall of all major blood vessels in the developing embryo, including those that form the perineural vascular plexus. Expression in the postnatal brain is confined to a scattered cell population within the vessel wall of small to medium-sized penetrating arteries, which are the vessel type primarily affected in CADASIL patients. In contrast, no expression was observed in capillaries and veins. Notch 3 is most likely expressed in a subset of vascular smooth muscle cells, and the expression pattern of one of the Notch ligands, Serrate 1, was very similar to that observed for Notch 3. The Notch 3 expressing pattern was not significantly altered in platelet-derived growth factor B- (PDGF-B) deficient mouse embryos, demonstrating that Notch 3 expression is not under direct control of PDGF-B. These data show that Notch 3 expression is conserved between mouse and human and suggest that the mouse is a valid system for analysis of CADASIL.
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PMID:Mouse Notch 3 expression in the pre- and postnatal brain: relationship to the stroke and dementia syndrome CADASIL. 1212 55

The Notch family of receptors and ligands plays an important role in cell fate determination, vasculogenesis, and organogenesis. Mutations of the Notch-3 receptor result in an arteriopathy that predisposes to early-onset stroke. However, the functional role of the Notch signaling pathway in adult vascular smooth muscle cells (VSMCs) is poorly characterized. This study documents that the Notch-3 receptor, the ligand Jagged-1, and the downstream transcription factor, HESR-1, are expressed in the normal adult rat carotid artery, and that this expression is modulated after vascular injury. In cultured VSMCs, both angiotensin II and platelet-derived growth factor (PDGF) markedly downregulated Notch-3 and Jagged-1 through ERK-dependent signaling mechanisms and prevented the glycosylation of Jagged-1. The downregulation of Jagged-1 and Notch-3 was associated with a decrease in CBF-1-mediated gene transcription activation and a fall in the mRNA levels of the downstream target transcription factor HESR-1. To test the hypothesis that the Notch pathway was coupled to growth regulation, we generated VSMC lines overexpressing the constitutively active form of Notch-3 (A7r5-N3IC). These cells exhibited a biphasic growth behavior in which the growth rate was retarded during the subconfluent phase and failed to decelerate at postconfluence. The lack of cell-cycle arrest in postconfluent A7r5-N3IC was associated with an attenuated upregulation of the cell-cycle inhibitor p27(kip) relative to control cells. This study documents the regulation of the Jagged-1 and Notch-3 genes in VSMCs by growth factor stimulation as well as a role for Notch-3 as a determinant of VSMC growth.
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PMID:Determinants of Notch-3 receptor expression and signaling in vascular smooth muscle cells: implications in cell-cycle regulation. 1245 85


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