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

Structural changes within the blood vessel wall such as hyperplasia and hypertrophy of vascular smooth muscle cells are important factors in the pathogenesis of hypertension. Humoral growth factors such as angiotensin II (AII) and platelet-derived growth factor BB (PDGF-BB) may participate in the remodelling of the blood vessel wall. Whether and by which mechanisms antihypertensive treatment is capable of influencing the structural blood vessel alterations to date remains unclear. In the present study, the effect of nifedipine and diltiazem on AII- and PDGF-BB-induced vascular smooth muscle cell proliferation was examined. Nifedipine and diltiazem at a concentration of 10 microM did not affect baseline DNA synthesis in isolated vascular smooth muscle cells in culture. AII (final concentration 100 nM) and PDGF-BB (50 ng/ml) stimulated DNA synthesis by approximately 9.0- and 4.6-fold, respectively. Both AII- and PDGF-BB-induced DNA synthesis was significantly blunted by diltiazem and nifedipine in a concentration of 10 microM, while no significant influence was seen with concentrations from 10 nM up to 1 microM. In contrast, no significant influence of these drugs could be observed on fetal calf serum 5%-induced DNA synthesis. The findings indicate that calcium antagonists possess antimitogenic potential and that they may thus contribute to the regression of structural changes of the blood vessels associated with hypertension.
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PMID:Inhibition of angiotensin II and platelet-derived growth factor-induced vascular smooth muscle cell proliferation by calcium entry blockers. 131 27

Essential hypertension and non-insulin-dependent diabetes mellitus are both associated with hyperinsulinemia and it has been proposed that this might contribute to increased atherogenesis in these conditions. In hypertension, hyperinsulinemia probably reflects reduced insulin-stimulated glucose uptake, but the reason for this, and the contribution of hyperinsulinemia (or of resistance to insulin) to the development of hypertension and atheroma, remains unclear. As well as glucose uptake, insulin has important effects on other aspects of cell function; for example, the hormone is an important regulator of the expression and function of the major inhibitory guanine nucleotide binding protein Gi. In insulin deficiency, Gi levels and function are greatly reduced and are restored by insulin treatment. We have examined whether in human hypertension or in animal models of hypertension there is evidence of abnormal regulation of this protein. Platelet membranes from humans and rat membranes from a range of tissues, including myocardium and vasculature, were studied. No alteration in Gi levels or function was found in these studies, and there is no evidence that this aspect of insulin action on cell function is abnormal. Insulin is also involved in the regulation of cell growth, and in vascular smooth muscle cells there is evidence that this effect involves action of other growth factors, such as PDGF. If the growth regulatory actions of insulin are also unimpaired despite limitation of insulin-stimulated glucose uptake, chronic hyperinsulinemia could lead to increased vascular smooth muscle cell growth and contribute to development of atheroma.
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PMID:Hypertension, insulin, and atherogenesis. 172 42

The pregnancy disorder preeclampsia continues as a major cause of maternal and infant mortality and morbidity. Despite intensive research since its recognition 100 years ago, our lack of understanding is evidenced by therapy which remains empiric, early delivery. Part of our failure to more completely understand the syndrome is due to excessive attention to the blood pressure elevation which accompanies the disorder, to the exclusion of a panoply of other physiologic aberrations. Although hypertension, if markedly elevated, can lead to maternal morbidity, it is not usually an important contributor to the pathophysiology of preeclampsia. It is primarily important as a marker for vasoconstriction, which in association with activation of coagulation reduces perfusion to many organs, including the fetal-placental unit. The earliest and likely most important pathophysiologic change is reduced placental perfusion secondary to abnormal implantation and/or a relative increase in placental mass. We propose that reduced placental perfusion results in the production of agent(s) by this organ, which injures or activates endothelial cells. The resulting endothelial cell dysfunction increases sensitivity to normal endogenous pressors, activates the coagulation cascade, and increases vascular permeability. These changes produce the characteristic pathophysiologic changes of the disorder. Evidence supporting this hypothesis includes abnormal endothelial morphology long recognized in glomerular capillaries, increased circulating fibronectin, and increased plasma mitogenic activity that long antedates the clinical disorder. In addition, an agent(s) is present in the blood of these women which activates endothelial cells in vitro as evidenced by increased release of [51Cr] chromium and increased production of PDGF. Preeclampsia is clearly more than "pregnancy induced hypertension."
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PMID:Clinical and biochemical evidence of endothelial cell dysfunction in the pregnancy syndrome preeclampsia. 193 Aug 53

Aortic vascular smooth muscle cells isolated from spontaneously hypertensive rats (SHR) replicate in vitro nearly twice as fast as cells isolated from several normotensive control strains of rats. Serum-derived peptide growth factors are known to stimulate cells to enter the DNA synthetic phase of the cell cycle and subsequent mitosis. We have examined the effect of several peptide growth factors to stimulate [3H]thymidine incorporation into DNA in smooth muscle cells isolated from adult (24 wk, hypertensive) SHR and age matched normotensive NIH Black Wistar (NBR) control rats. Our results indicate that the response of the SHR cells to epidermal growth factor (EGF) is selectively enhanced compared to the control NBR cells. PDGF also stimulated DNA synthesis but no significant difference between SHR and NBR was observed. Nerve growth factor and endothelial derived growth factor were not mitotic on either cell line. Additionally, we have found that SHR cells, isolated from young early hypertensive weanling animals before a significant elevation in pressure has occurred, divide at the same rate as adult SHR cells normotensive strains. These results are consistent with the view that genetic changes affecting the cellular response to EGF may influence the development of early hypertensive hyperplasia in the SHR which in concert with other factors aggravates the later development of hypertension.
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PMID:Selectively enhanced stimulation of DNA synthesis by EGF in vascular smooth muscle cells from young and adult SHR. 235 36

Current concepts of the pathogenesis of atherosclerosis have been reviewed, emphasizing some of the similarities of the mechanisms and events involved to those in inflammation. Figure 2 is a schematic summary of these events. Hyperlipidemia, or some component of hyperlipidemic serum, as well as other risk factors, are thought to cause endothelial injury, resulting in adhesion of platelets and/or monocytes and release of PDGF (and other growth factors), which leads to smooth muscle migration and proliferation. It is clear that endothelial injury need not be denuding, and in fact may consist of altered endothelial function (dysfunction); adhesion of monocytes, increased permeability of endothelium, and disturbances in growth control can occur without morphologically obvious endothelial injury. Hyperlipidemia, hypertension, smoking, immune injury, and other risk factors may contribute to this endothelial dysfunction in different ways and sometimes in combination. Smooth muscle cells produce large amounts of collagen, elastin, and proteoglycans and these form part of the atheromatous plaque. Hyperlipidemia contributes in a number of ways (as discussed earlier), and indeed, in the severely hypercholesterolemic patient, such as one with familial hypercholesterolemia, is alone sufficient to cause atherosclerosis in the absence of other risk factors. Foam cells of atheromatous plaques are derived both from macrophages and from smooth muscle cells; from macrophages via the beta-VLDL receptor and also possibly by way of LDL modification, recognized by the acetyl-LDL receptor (such as oxidized LDL); and from smooth muscle cells by less certain mechanisms. Extracellular lipid is derived from insudation from the lumen, particularly in the presence of hypercholesterolemia, and also from degenerating foam cells. Cholesterol accumulation in the plaque should be viewed as reflecting imbalance between influx and efflux, and it is possible that high-density lipoprotein is the molecule which helps clear the cholesterol from these accumulations (134). The diagram (right) also depicts the possibility that smooth muscle proliferation may occur without endothelial injury at all. There are several postulated mechanisms for such an occurrence: loss of growth control, direct smooth muscle injury (such as by LDL), and autonomous proliferation by the mechanisms suggested by Benditt. The theoretical scheme presented is based largely on in vitro work, only partly substantiated by experimental and human studies, and does not explain the precise mechanisms by which all risk factors increase the susceptibility to atherosclerosis.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The pathogenesis of atherosclerosis: atherogenesis and inflammation. 327 59

Although lipids have received most attention in relation to atherosclerosis, vessel injury also has a role in the development of atherosclerotic lesions. Thrombi that form at sites of injury can be incorporated into the wall, causing thickening, and platelets that adhere to damaged vessel walls release a growth factor (PDGF) that stimulates smooth muscle cell proliferation. The early lesions of atherosclerosis are focal and develop around vessel orifices and branches in relation to the patterns of blood flow and areas of increased permeability and endothelial cell damage. Platelets also contribute to the complications of advanced atherosclerosis caused by occlusive thrombi, thromboembolism, and spasm. The causes of vessel wall injury are not established, although there is evidence pointing to disturbed blood flow, hypertension, antigen--antibody complexes, complement, materials originating from platelets and white blood cells, bacteria, endotoxin, viruses, smoking, dietary lipids, homocystinemia, diabetes, other metabolic disorders, and stress. Platelets do not adhere to intact endothelium, but they adhere to the constituents of the subendothelium, release the contents of their granules (including PDGF), and form thromboxanes. If blood flow is disturbed, platelet--fibrin thrombi can form at sites of injury. Platelet adherence to a damaged wall does not require von Willebrand factor except under conditions of high wall shear. Repeated injury of a vessel wall leads to the development of lipid-rich atherosclerotic lesions, even in normocholesterolemic animals, but these lesions do not form if the experimental animals are made thrombocytopenic before injury is induced. Measurable changes in platelets that are associated with the clinical complications of atherosclerosis include shortened survival, release of granule contents (platelet factor 4, beta-thromboglobulin, thrombospondin), formation of thromboxanes, and decreased buoyant density. "Antiplatelet drugs" such as aspirin are proving to be beneficial in selected groups of patients, such as those with unstable angina. Thromboxane synthetase inhibitors and agents that block the thromboxane receptor on platelets are under investigation. Long term administration of "antiplatelet drugs" to affect the rate of development of atherosclerosis seems neither feasible nor desirable. Modification of dietary and smoking habits and control of hypertension are more likely to be beneficial for most individuals.
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PMID:The role of platelets in the development and complications of atherosclerosis. 351 36

At least two exogenous sources of agents able to control vascular smooth muscle proliferation can be identified. Platelets contain and release mitogens as well as a factor, TGF-beta, that inhibits cell growth on plastic surfaces while stimulating it when cells are grown in suspension in soft agar. Macrophages release mitogens, including PGDF, and macrophage invasion is characteristic of early experimental lesions in fat-fed animals. Finally, it is at least possible that endothelial cell production of mitogens may represent a response to some as yet undefined external injury. The vessel wall also offers sources of growth control endogenous to the smooth muscle cell layers. The vessel wall contains heparan sulfate able to inhibit cell growth of smooth muscle cells, which by themselves can synthesize PDGF. This provides possible positive and negative control of replication intrinsic to the smooth muscle cells themselves. The role of these intrinsic or extrinsic factors in the smooth muscle proliferation of hypertension and atherosclerosis remains hypothetical. It is intriguing to implicate platelets and/or macrophages in the denuding injuries seen in small hypertensive vessels and in advancing atherosclerotic plaques. At least for the latter case, however, there seem to be other critical factors. Simple denudation and thrombosis, for example, are not sufficient to stimulate smooth muscle growth, and the kinetics of proliferation after balloon denudation imply the presence of some other event required to initiate smooth muscle proliferation. Similarly, smooth muscle replication in large vessels of hypertensive animals occurs without loss of endothelial continuity. This implies that replication in response to hypertension depends on factors intrinsic to the vessel wall. Benditt's observation of monoclonality also implies some intrinsic mechanism allowing cells to grow in a focal manner. It is intriguing to consider the possibility that this commitment process could require the release of cells from the intrinsic inhibitory effects of heparan sulfate located around the cells or the synthesis of growth factors secreted by the smooth muscle cells themselves. If we add the hypothesis that only some cells are capable of such a response, we would expect the sort of oligodense phenomenon demonstrated by Benditt. Proof of such a hypothesis, however, will have to await development of methods to explore these mechanisms directly in the vessel wall responding to injury.
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PMID:Common mechanisms of proliferation of smooth muscle in atherosclerosis and hypertension. 354 73

We have tried to compare the proliferative responses seen in two vascular diseases: atherosclerosis and hypertension. Both diseases involve endothelial injury and proliferation, but our knowledge of this phenomenon is just beginning to emerge. In atherosclerosis the best evidence is that denudation does not occur in the normal young animal. Man, however, ages over a much longer time than our usual animal models, and the study of denudation during the chronic progression of atherosclerotic lesions remains to be done. We need to consider the possibility that repetitive, small lesions may occur at sites of endothelial turnover. We also need to know more about the possible role of nondenuding injuries, including death of endothelial cells in situ and the apparent increased stickiness of endothelial cells and monocytes during the early stages of hypercholesterolemia. The role of endothelial injury in hypertension also needs more study. We know that extensive denudation and thrombosis occur in small vessels subjected to high blood pressure. It is highly probable that release of PDGF occurs at these sites, possibly accounting for the characteristic hyperplasia seen in malignant hypertension. Whether this process is related to the more subtle changes in vessel wall mass seen in chronic hypertension remains unknown. Finally, there are remarkable differences in the proliferative behavior of the smooth muscle cells themselves in these two diseases. Hypertensive vascular disease is, in large part, a disease of the media. Atherosclerosis is characterized by intimal hyperplasia. Injury results in migration of smooth muscle cells from the media and cell division in the intima. It is possible to identify chemotactic factors using putative atherosclerosis risk factors or normal components of serum. This has already been done for one component of lesion formation, PDGF, and there is a report of a monocyte chemotactic factor released by smooth muscle cells. Factors released by other components of lesions may be of considerable interest. In contrast, changes in hypertension occur within a more orderly preservation of vessel wall structure. The wall thickens, but this occurs by increased synthesis of cell mass in the media. The cells themselves do not even divide, but they undergo a form of amitotic replication of their DNA.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cellular proliferation in atherosclerosis and hypertension. 637 94

To clarify the role of PDGF A-chain in hypertensive vascular hypertrophy of spontaneously hypertensive rats (SHRs), we studied levels of PDGF A-chain gene expression and transcription factors related to the gene in vascular smooth muscle cells (VSMCs) of SHRs in vivo. RNase protection assay and in situ hybridization showed that PDGF A-chain mRNA levels in VSMCs of SHRs were twofold higher than in those of normotensive Wistar-Kyoto rats. Gel retardation assays showed that levels of Sp1 and AP-2 in VSMCs of SHRs were twofold more abundant than in those of Wistar-Kyoto rats. Treatment with four pharmacologically different species of antihypertensive drugs for 2 wk decreased the levels of both PDGF A-chain mRNA and Sp1, but not AP-2 level in VSMCs of SHRs with regression of aortic hypertrophy, indicating that increases in levels of both PDGF A-chain mRNA and Sp1 in VSMCs of SHRs were associated with high blood pressure. These results suggest that high blood pressure is a stimulus which upregulates PDGF A-chain gene expression in VSMCs of SHRs, resulting in an autocrine enhancement in hypertensive vascular hypertrophy, and that the activation of the gene may be mediated through increases in Sp1 in these cells.
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PMID:Blood pressure regulates platelet-derived growth factor A-chain gene expression in vascular smooth muscle cells in vivo. An autocrine mechanism promoting hypertensive vascular hypertrophy. 788 63

The effects of carvedilol, a novel cardiovascular agent, were evaluated in developing spontaneously hypertensive rats (SHR) for effects on hemodynamics, and the ability to effect the development of left ventricular, and vascular hypertrophy associated with chronic hypertension. Chronic oral administration of low dose carvedilol (20 mg/kg/day) was initiated when rats were 5 weeks of age, and experiments progressed until 14 weeks of age. Carvedilol-treated SHR had significantly reduced systolic blood pressures and heart rates throughout the duration of the experiment, and had significantly reduced ventricle/body weights by approximately 9.0%. Morphologic analysis of tertiary branches of the mesenteric artery revealed that carvedilol-treated SHR had significant reductions in medial cross-sectional area. Carvedilol produced concentration-dependent inhibition of basal [3H]thymidine incorporation in cultured SHR vascular smooth muscle cells, as well as by stimulation produced by PDGF (1 nM), EDGF (1 nM), thrombin (0.5 U/ml), or endothelin-1 (1 nM), indicating that carvedilol had direct anti-mitogenic activity. The present studies demonstrate that low dose carvedilol produced sustained reductions in blood pressure and heart rate in developing SHR that were accompanied by significant inhibition in the development of vascular and myocardial hypertrophy. The morphological changes induced by carvedilol may be mediated by a combination of hemodynamic effects, as well as by direct anti-mitogenic effects on vascular smooth muscle.
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PMID:Carvedilol, a novel cardiovascular agent, inhibits development of vascular and ventricular hypertrophy in spontaneously hypertensive rats. 819 8


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