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

The development of laboratory techniques for the culturing of vascular endothelial and smooth-muscle cells during the 1970s, followed by the rapid advances in molecular and cell biology during the 1980s, provided the foundation for the identification of growth factor and cytokine networks involved in maintenance of the normal vasculature as well as participating in diverse pathologic processes involving blood vessels. Vascular cells can produce and respond to a vast array of biochemical messengers that control cell replication, differentiation, and many specific cell functions. Investigators are beginning to explore the changes in the patterns of messengers exchanged between the vascular cells and infiltrating leukocytes during the initiation and progression of atherosclerosis. A variety of in vitro and in vivo studies have indicated that growth factors and cytokines that mediate the critical processes of inflammation and wound healing also play a central role in vascular disease. Indeed, many view atherosclerosis as the result of excessive or prolonged chronic inflammation and wound healing in response to diverse injurious stimuli to cells of the vessel wall. Vascular injury may result from many varied and interacting forces, including nutritional and metabolic abnormalities such as hyperlipidemias or elevated homocysteine, mechanical forces associated with hypertension, exogenous toxins including those found in cigarette smoke, abnormally glycated proteins associated with diabetes mellitus, oxidatively modified lipids or proteins, and, possibly, viral infections. Ultimately, a greater understanding of the activated cytokine and growth factor networks within the vascular wall following injury and during atherogenesis will allow clinical scientists to identify steps susceptible to therapeutic intervention using recombinant cytokines, antibodies, soluble receptors, or receptor antagonists. Other therapeutic strategies may involve the transfection of specific genes, which may inhibit atherosclerosis, into vascular cells at sites prone to lesion formation.
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PMID:Cytokines and growth factors in atherogenesis. 145 74

While the roles of the platelet-derived growth factors (PDGFs) in vascular smooth muscle cells (SMCs) continue to be elucidated, these cells, especially in their activated 'synthetic' state, have also been found to express, and proliferate in response to, many of the other families of polypeptide growth factors, such as the fibroblast growth factors. Other stimulators of DNA synthesis, and particularly of SMC hypertrophy, include the vasoconstrictor hormones such as angiotensin II, as well as physical forces, especially stretch or tension. For many of these ligands, multiple receptors have been identified and their means of signal transduction are being characterized rapidly. Regulatory regions of these genes are being identified as are transcription factors. Complex post-transcriptional regulation has also been shown by the findings that some growth factors are phosphorylated, or translocated to the nucleus or the extracellular matrix. Inhibitors have also been identified. These include some prostaglandins, calcium antagonists, agonists that activate guanylate and adenylate cyclases, inhibitors of angiotensin-converting enzyme, interferon gamma, and heparin. Future studies are likely to show that tyrosine phosphatases and recessive oncogenes also regulate growth. The existence of so many autocrine/paracrine mitogens--together with some experimental data--suggests some redundancy in the system as well as some additive effects. Redundancy may limit the efficacy of antibodies to a single growth factor to block cell proliferation. Their evolutionary conservation implies some unique roles for each growth factor but these have not been apparent from in vitro studies to date. Further insights are apt to come from the increasing recognition that growth factors have other effects--on cell attachment, migration, survival, production of extracellular matrix, thrombosis, vaso-constriction, regulation of cytokine synthesis, and inhibition of growth. Many of these effects may prove to be context-dependent, as with the case of growth inhibition by transforming growth factor-beta. Studies in monolayer cultures may not obtain the same results as studies using cocultures of endothelial and smooth muscle cells, or 3-dimensional matrix cultures, organ cultures, or in the intact animal. In vivo descriptive studies of growth factors expressed in vascular embryogenesis, hypertension, atherosclerosis, acute balloon injury and thrombosis are being supplemented by interventions such as infusions with growth factors, antibodies, and toxin conjugates. These studies, and studies using transgenic mice and homologous recombination, should yield information as to mechanisms and may also suggest new therapies.
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PMID:Smooth muscle cell growth factors. 181 90

The endothelium is a regulatory organ that mediates hemostasis, contractility, cellular proliferation, and inflammatory mechanisms in the vessel wall. Injury to the endothelium from hypertension, smoking, hyperlipidemia, and diabetes mellitus disrupts normal regulatory properties and results in abnormal endothelial cell function. Clinically, endothelial cell dysfunction can be manifested as vasospasm, thrombus formation, atherosclerosis, or restenosis. The normal hemostatic properties of the endothelium include the maintenance of a nonadhesive luminal surface, antithrombotic properties, anticoagulant properties, and fibrinolytic properties. The endothelial cell regulates smooth muscle cell contractility by the production of relaxing and constricting factors in response to physiologic stimuli. Endothelial cell injury is also an initial event in the development of atherosclerosis and restenosis by facilitating platelet adhesion and aggregation and by signaling the release of mitogens from platelets, macrophages, and endothelial cells, which stimulate smooth muscle cell proliferation. In addition, endothelial cells undergo morphologic and functional alterations in response to cytokine signals, which may contribute to the pathogenesis of vasculitis and atherosclerosis. In sum, the normal endothelium performs many regulatory functions which become altered when the endothelium is injured.
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PMID:Biology of the impaired endothelium. 195 Nov 6

In chronic models of hypertension such as the spontaneously hypertensive rat (SHR), thickening of the media of large arteries occurs mainly through smooth muscle cell (SMC) hypertrophy accompanied by DNA replication resulting in large polyploid cells. In resistance vessels of SHR, medial hypertrophy occurs through a hyperplastic response. It has been suggested that this hyperplasia is due to mitogens such as platelet-derived growth factor (PDGF), while the hypertrophied polyploid cells occur from stimulation by angiotensin II from within the vessel wall. Angiotensin II activates many of the same cellular pathways as PDGF, including stimulation of phospholipase C, mobilization of intracellular calcium and activation of Na+/H+ exchange. Both induce transient increases in the proto-oncogenes c-fos and c-myc. However, a possible explanation for the difference in SMC response may be involvement of an intracellular pathway stimulated by PDGF (but not by angiotensin II), such as stimulation of JE (a cytokine-like molecule), which may activate transcriptional events necessary for mitogenesis. In atherosclerosis vascular hypertrophy occurs in the form of focal intimal thickening and results from hyperplasia of diploid SMC and their greatly increased production of extracellular matrix, (particularly collagen) and the accumulation of intra- and extracellular lipid. The SMC involved in atherogenesis are phenotypically modified compared with the SMC of undiseased regions, and amongst other features have a lower volume fraction of myofilaments (Vvmyo). Associated with modulation to a low Vvmyo are increases in SMC expression of mRNA for collagens type I (alpha 1 and alpha 2) and type III (alpha 1), elastin, fibronectin, as well as massive increases in collagen protein (26- to 45-fold), glycosaminoglycans (5-fold), and lipid accumulation (7-fold).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular biology of vascular hypertrophy. 203 94

Transforming growth factor-beta, a peptide growth factor, is known to be a multifunctional regulator of cellular activity. The effect of this growth factor on extracellular matrix formation is well established, but its effects on elastin, a critical component of lung, skin, and blood vessels are unknown. In the present study, by use of an Enzyme-Linked Immunoassay method, we found that transforming growth factor-beta strongly increased elastin production in cultured porcine aortic smooth muscle cells. In a dosage-dependent study, 1.0-10.0 ng/ml transforming growth factor-beta promoted elastin production 2-3 fold. In a time-dependent study, at least an 8 h pre-treatment with 10.0 ng/ml transforming growth factor-beta was required for sustained increases in elastin production. The effects of transforming growth factor-beta on cultured aortic smooth muscle cells suggest that this cytokine may be an important mediator of elastin formation during atherosclerosis and hypertension.
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PMID:The elastogenic effect of recombinant transforming growth factor-beta on porcine aortic smooth muscle cells. 316 37

In cultured vascular smooth muscle cells, the baseline mRNA and protein levels of an inducible type of nitric oxide synthase were barely detectable. Interferon gamma, tumor necrosis factor-alpha, and interleukin-1 beta each markedly increased mRNA and protein levels of this enzyme in parallel with the production of nitrite, a stable oxidative metabolite of nitric oxide. Actinomycin D abolished the cytokine-induced increases in mRNA levels and nitrite production. Cycloheximide, which abolished the cytokine-induced increase in nitrite production, had no effect on the interferon-gamma-induced increase in mRNA levels but partially inhibited that induced by interleukin-1 beta and markedly inhibited that induced by tumor necrosis factor-alpha. Transforming growth factor-beta 1, which inhibited the interferon gamma-, interleukin-1 beta-, and tumor necrosis factor-alpha-induced nitrite production, did not affect the increases in mRNA levels caused by these cytokines. Transforming growth factor-beta 1, however, significantly inhibited the increase in protein levels caused by these cytokines. These findings suggest that interferon gamma directly induces the expression of the inducible nitric oxide synthase gene, whereas tumor necrosis factor-alpha and interleukin-1 beta induce it, at least in part, via the induction of intermediary protein(s), and that transforming growth factor-beta 1 inhibits cytokine-induced nitric oxide production by blocking the posttranscriptional synthesis of inducible nitric oxide synthase.
Hypertension 1994 Jan
PMID:Expression of nitric oxide synthase by cytokines in vascular smooth muscle cells. 750

Impaired neutrophil responses contribute to the neonate's increased susceptibility to infection. Because granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) enhance granulocyte and macrophage number and function, their use in the management of neonatal sepsis may be beneficial. Little is known about the endogenous levels of G-CSF and GM-CSF. In adults, raised values for G-CSF, but not GM-CSF, have been demonstrated in patients with infection, and conflicting data has emerged regarding CSF levels in neonates. We have used an ELISA to measure maternal and cord serum G-CSF and GM-CSF at the time of delivery, with gestational age between 25 and 42 wk. In mothers, an inverse linear relationship between gestational age and GM-CSF levels (p = 0.049) was found, but no association with G-CSF levels was observed. In neonates, a quadratic association was found between GM-CSF levels and gestational age (p = 0.019), whereas G-CSF levels showed an inverse linear association (p = 0.015). In addition, an association was found between maternal and cord GM-CSF (p = 0.007) but not G-CSF levels in paired samples. The effect of gestational age on the cytokine levels could not be explained by the white cell count, the absolute neutrophil count, pregnancy-induced hypertension, or the presence of infection.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Granulocyte and granulocyte-macrophage colony-stimulating factors in cord and maternal serum at delivery. 751 77

Nitric oxide (NO) is an important intercellular signaling molecule synthesized in diverse human tissues by proteins encoded by a family of NO synthase (NOS) genes. The similarity of sequence and cofactor binding sites has suggested that the NOS genes may also be related to cytochrome P450 reductase, as well as to plant and bacterial oxidoreductases. Endothelial NOS activity is a major determinant of vascular tone and blood pressure, and in several important (and sometimes hereditary) disease states, such as hypertension, diabetes, and atherosclerosis, the endothelial NO signaling system appears to be abnormal. To explore the relationship of the endothelial NOS gene to other similar genes, and to delineate the genetic factors involved in regulating endothelial NOS activity, we isolated the human gene encoding the endothelial NOS. Genomic clones containing the 5' end of this gene were identified in a human genomic library by applying a polymerase chain reaction (PCR)-based approach. Identification of the human gene for endothelial NOS (NOS3) was confirmed by nucleotide sequence analysis of the first coding exon, which was found to be identical to its cognate cDNA. The NOS3 gene spans at least 20 kb and appears to contain multiple introns. The transcription start site and promoter region of the NOS3 gene were identified by primer extension and ribonuclease protection assays. Sequencing of the putative promoter revealed consensus sequences for the shear stress-response element, as well as cytokine-responsive cis regulatory sequences, both possibly important to the roles played by NOS3 in the normal and the diseased cardiovascular system.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Isolation and chromosomal localization of the human endothelial nitric oxide synthase (NOS3) gene. 751 68

Three isozymes of nitric oxide (NO) synthase (EC 1.14.13.39) have been identified and the cDNAs for these enzymes isolated. In humans, isozymes I (in neuronal and epithelial cells), II (in cytokine-induced cells), and III (in endothelial cells) are encoded for by three different genes located on chromosomes 12, 17, and 7, respectively. The deduced amino acid sequences of the human isozymes show less than 59% identity. Across species, amino acid sequences for each isoform are well conserved (> 90% for isoforms I and III, > 80% for isoform II). All isoforms use L-arginine and molecular oxygen as substrates and require the cofactors NADPH, 6(R)-5,6,7,8-tetrahydrobiopterin, flavin adenine dinucleotide, and flavin mononucleotide. They all bind calmodulin and contain heme. Isoform I is constitutively present in central and peripheral neuronal cells and certain epithelial cells. Its activity is regulated by Ca2+ and calmodulin. Its functions include long-term regulation of synaptic transmission in the central nervous system, central regulation of blood pressure, smooth muscle relaxation, and vasodilation via peripheral nitrergic nerves. It has also been implicated in neuronal death in cerebrovascular stroke. Expression of isoform II of NO synthase can be induced with lipopolysaccharide and cytokines in a multitude of different cells. Based on sequencing data there is no evidence for more than one inducible isozyme at this time. NO synthase II is not regulated by Ca2+; it produces large amounts of NO that has cytostatic effects on parasitic target cells by inhibiting iron-containing enzymes and causing DNA fragmentation. Induced NO synthase II is involved in the pathophysiology of autoimmune diseases and septic shock. Isoform III of NO synthase has been found mostly in endothelial cells. It is constitutively expressed, but expression can be enhanced, eg, by shear stress. Its activity is regulated by Ca2+ and calmodulin. NO from endothelial cells keeps blood vessels dilated, prevents the adhesion of platelets and white cells, and probably inhibits vascular smooth muscle proliferation.
Hypertension 1994 Jun
PMID:Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions. 751 53

Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional cytokine capable of regulating the growth and differentiation of many cell types, as well as regulating their environment in the blood vessel wall. Its production by endothelium and/or vascular smooth muscle is stimulated by biophysical forces, growth factors and also vasoconstrictors. In hypertension TGF-beta 1 gene transcription is most likely elevated by a combination of physical and chemical stimuli with the cytokine acting to increase the production of extracellular matrix proteins or to modulate smooth muscle cellular growth, producing hypertrophy, polyploidy or proliferation. With respect to the latter, TGF-beta 1 potentiates the proliferative effects of many receptor tyrosine kinase-activating growth factors in vascular smooth muscle from SHR, but inhibits such proliferation in WKY smooth muscle. It also differentially affects collagen production by the two cell types. It is suggested that the augmented proliferative response in renal hypertensive SHR, compared to renal hypertensive WKY, is the consequence of these differential effects of TGF-beta 1 on smooth muscle cell proliferation. TGF-beta 1 is also likely to be a significant contributor to the development of vascular hypertrophy in genetic hypertension.
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PMID:Transforming growth factor-beta 1 and the development of vascular hypertrophy in hypertension. 758 73


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