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 effects of prolactin (PRL) on A10 (aortic smooth muscle) cell proliferation were examined by measuring both [3H]thymidine incorporation and increases in cell number. PRL induced a significant proliferative response from 10(-11) to 10(-7) M, with optimal activity at 10(-10) M. PRL also enhanced platelet-derived growth factor (PDGF)-induced proliferation. The possibility that PRL induces proliferation through a protein kinase C (PKC)-mediated mechanism was also examined. PRL caused activation of PKC from 10(-12) to 10(-8) M. Antiserum to PRL, a monoclonal antibody directed against the PRL receptor and the immunosuppressive agent cyclosporine A, were able to inhibit PRL-induced proliferation and activation of PKC. The PKC inhibitors, staurosporine, sphingosine, and 1-(-5-iso-quinoline-sulfonyl)-2-methylpiperazine (H-7) also antagonized both proliferation and PKC activation. These data strongly suggest that PRL-induced A10 cell proliferation is mediated through the PKC pathway and that this may play a role in vascular smooth muscle cell hyperplasia, characteristic of the pathogenesis of cardiovascular diseases such as hypertension and atherosclerosis.
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PMID:Prolactin induces proliferation of vascular smooth muscle cells through a protein kinase C-dependent mechanism. 186 Aug 93

The increased growth potential of vascular smooth muscle cells (VSMCs) represents one of the crucial anomalies responsible for the development of essential hypertension, diabetic macroangiopathy, and atherosclerosis. The exaggerated response to growth factors of VSMC from spontaneously hypertensive rats (SHRs) persists in culture when compared with normotensive Wistar-Kyoto control rats, indicating an intrinsic defect in the hypertension-producing mechanism. This greater proliferation is characterized by two intermediate phenotypes: (1) accelerated entry into the S phase of the cell cycle, which results from hyperresponsiveness to epidermal growth factor and platelet-derived growth factor, and (2) abnormal contact inhibition. The enhanced expression of transforming growth factor beta 1 (TGF-beta 1) messenger ribonucleic acid in SHRs precedes this altered contact inhibition, and only VSMCs from SHRs respond to exogenously added TGF-beta 1 at a high cell density, which suggests that abnormal TGF-beta 1 autoregulation may be implicated in the second phenotype. Platelets contain major growth factors for VSMC. Platelet extracts from hypertensive and diabetic patients present augmented growth-promoting activity on VSMCs, which is most evident when both diseases occur simultaneously. Growth-promoting activity may be further influenced by antihypertensive therapy. This growth-promoting activity is increased by hydrochlorothiazide but not by indapamide, atenolol, or captopril in diabetic hypertensive and nondiabetic hypertensive patients. In conclusion, VSMCs in hypertension manifest an intrinsic growth defect that is modulated by extrinsic platelet growth factors and antihypertensive drugs.
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PMID:Vascular smooth muscle cell proliferation and its therapeutic modulation in hypertension. 192 87

Arterial wall injury either by balloon catheter, drying, or scraping results in a denudation of endothelial cells (EC) and a subsequent proliferation of smooth-muscle cells (SMC). The degree of SMC proliferation appears to be dependent on the degree of initial injury and not to the loss of the overlying endothelium. Successful reendothelialization of denuded areas depends on the size of the denuded segment as well as SMC-EC interactions. Prolonged exposure of SMC to serum substances results in inhibition of EC regrowth, the production of prostacyclin by SMC, and the development of a thromboresistant surface. Heparin appears to inhibit SMC proliferation in vivo (as well as in vitro), an effect that is independent of platelet SMC interaction. EC-derived heparin in vivo may also result in inhibition of SMC proliferation. Platelets may play an important role in the early response to arterial injury and development of myointimal hyperplasia (MIH), but their long-term role appears to be minor. Antiplatelet agents have widely varying species-dependent effects on platelets and platelet-vessel wall interactions, but in specific circumstances they may inhibit MIH. The precise role of steroid drugs and immunosuppression on MIH in arterial injury models awaits further study. The role of lipoproteins in MIH is unclear; however, the inhibition of MIH by omega-3 fatty acids in vivo as well as their inhibition of platelet-derived growth factor production by EC in vitro implies a regulatory role. Acute hypertension results in a marked proliferation of EC and SMC in vivo and enhances the proliferative response to injury as well. Low wall shear stress, turbulence, and boundary layer separation all increase EC turnover, a likely influence on EC growth factor production. The compliance mismatch resulting from graft-artery anastomoses, injury, and endarterectomy results in locally increased cyclical stretch, which may predispose to SMC proliferation.
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PMID:Myointimal hyperplasia: pathogenesis and implications. 2. Animal injury models and mechanical factors. 203 59

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

The increased potential for growth of vascular smooth muscle cells in one of the key abnormalities in the development of essential hypertension, diabetic microangiopathy and atherosclerosis. The underlying mechanisms seem to be extrinsic (increased platelet-derived growth factor-like activity) and intrinsic (increased rate of growth, greater maximal response to growth factors and less contact inhibition). In this article, the authors discuss the primary role of an alteration in vascular smooth muscle cellular proliferation in hypertension, the extrinsic growth factors contained in platelet extracts of diabetic and hypertensive subjects and the specific effects of insulin and antihypertensive therapy on this pro-mitotic platelet activity. The result of experimental studies in our laboratory and in other studies suggest that genetic factors and therapeutic intervention could control the growth of vascular smooth muscle cells and that further evaluation of anti-hypertensive therapy may be necessary.
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PMID:[Intrinsic and extrinsic factors implicated in cell proliferation of vascular smooth muscle in hypertension and diabetes]. 208 Aug 91

Endothelial cells play an important regulatory role in the circulation as a physical barrier and as a source of a variety of regulatory substances. Endothelium-derived nitric oxide and prostacyclin are released in response to physical stimuli, hormones and platelet-derived substances and induce vascular relaxation and inhibition of platelet function. Certain substances can evoke a hyperpolarization of smooth muscle cells. In addition, endothelial cells can release several contracting factors (i.e. endothelin, thromboxane A2, angiotensin II, superoxide and unidentified endothelium-derived contracting factors), at least under certain conditions. Endothelial cells are also a source of growth inhibitors and promoters, such as heparin and heparin sulphates, platelet-derived growth factor and thrombospondin. Several vasoactive substances produced by the endothelium, such as nitric oxide, endothelin and angiotensin II may also play a role in the regulation of vascular growth. Thus, the endothelial layer can regulate vascular tone and growth. A dysfunction of these endothelium-dependent regulatory systems may play a role in cardiovascular diseases, such as hypertension and atherosclerosis.
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PMID:Endothelial control of vascular tone and growth. 220 57

The cells that make up blood vessel walls appear to participate actively in local immune and inflammatory responses, as well as in certain vascular diseases. We tested here whether smooth muscle cells (SMC) can produce the important inflammatory mediator IL6. Unstimulated SMC in vitro elaborated 5 X 10(3) pg recIL6/24h (i.e., biological activity equivalent to 5 X 10(3) pg recombinant IL6 (recIL6), as determined in B9-assay with a recIL6 standard). Several pathophysiologically relevant factors augmented IL6 release from SMC including 10 micrograms LPS/ml (10(4) pg recIL6), 10 ng tumor necrosis factor/ml (4 X 10(4) pg recIL6), and most notably 10 ng IL1/ml (greater than or equal to 3.2 X 10(5) pg recIL6). Production of IL6 activity corresponded to IL6 mRNA accumulation and de novo synthesis. SMC released newly synthesized IL6 rapidly, as little metabolically labeled material remained cell-associated. In supernatants of IL1-stimulated SMC, IL6 accounted for as much as 4% of the secreted proteins. In normal vessels SMC seldom divide, but SMC proliferation can occur in hypertension or during atherogenesis. We therefore tested the relationship between IL6 production and SMC proliferation in response to platelet-derived growth factor (PDGF) in vitro. Quiescent SMC released scant IL6 activity, whereas PDGF (1-100 ng/ml) produced concentration-dependent and coordinate enhancement of SMC proliferation and IL6 release (linear regression of growth vs. IL6 release yielded r greater than 0.9). IL6 itself neither stimulated nor inhibited SMC growth or IL6 production. Intact medial strips studied in short-term organoid culture produced large quantities of IL6, similar to the results obtained with cultured SMC. These findings illustrate a new function of vascular SMC by which these cells might participate in local immunoregulation and in the pathogenesis of various important vascular diseases as well as in inflammatory responses generally.
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PMID:Proliferating or interleukin 1-activated human vascular smooth muscle cells secrete copious interleukin 6. 231 24

Approximately 5.8 million people in the United States have been diagnosed by a physician as being diabetic, and an additional 4 to 5 million people have undiagnosed diabetes. Although the incidence of diabetes appears to be declining from a peak of 300 per 100,000 population in 1973, to 230 per 100,000 in 1981, its prevalence continues to rise, due to a 19 percent decline since 1970 in deaths caused by diabetes. In 1982, 34, 583 deaths were attributed to diabetes, resulting in diabetes being ranked as the seventh leading underlying cause of death. Medical and surgical complications of diabetes due to macro- and microvascular disease result in 5,800 new cases of blindness, 4,500 perinatal deaths, 40,000 lower extremity amputations and 3,000 deaths due to diabetic coma (ketotic and hyperosmolar) and at least 4,000 new cases of end-stage renal disease. Hyperglycemia is a major if not sole determinant of diabetic glomerulopathy. The exact mechanism underlying diabetic vasculopathy is under intensive study. Experiments in the induced-diabetic rat and dog suggest that small vessel injury may--under defined circumstances--be associated with the polyol (sorbitol) pathway of glucose metabolism, myoinositol deficiency, capillary hypertension, plasma hyperviscosity, stiff erythrocytes, elevated circulating thromboxane, and platelet-derived growth factor(s). As yet, no single hypothesis fits these seemingly disparate pieces together into a unified formulation of the genesis of diabetic complications. Clinical experience sustains the contention that a functioning kidney transplant proffers the uremic diabetic younger than age 60 a higher probability for survival with good rehabilitation than does either peritoneal dialysis or maintenance hemodialysis. Diabetics treated by kidney transplantation require more than the routine preoperative and postoperative attention afforded to nondiabetic ESRD patients. During initial nephrologic evaluation, concurrent extrarenal vascular disease--especially ophthalmic, cardiovascular, cerebrovascular and in the extremities, often demands immediate attention. Inventory of co-morbid risk factors pre-transplant facilitates their management post-transplant, thereby improving chances for rehabilitation. Consultations with an ophthalmologist and podiatrist familiar with management of the uremic diabetic should be obtained prior to transplant surgery. When performed as a component of pre-transplant evaluation, coronary angiography permits identification and correction, in many patients, of potentially fatal coronary artery disease.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Renal failure in diabetes: a substantive problem in provision of health care. 267 7

In hypertension the small arteries undergo structural changes that increase vascular resistance, both in vivo and in vitro. The hallmark of a physiological vascular amplifier is that enhanced resistance responses must occur about the resting value. For this to happen, the average radius of the resistance vessels must be narrower than normal; increased wall thickness without narrowing does not result in this type of amplification. In primary hypertension in spontaneously hypertensive rats (SHR), the structural changes in the resistance vessels precede the elevation in blood pressure. This is consistent with the hypothesis that these changes cause hypertension. The role of the sympathetic nervous system in early vascular development is unclear, in view of the absence of regression of amplifier properties in the hindlimb vessels after extensive immunosympathectomy. However, short periods of enalapril treatment in young animals attenuate the development of hypertension and normalize hindlimb resistance properties, suggesting that the renin-angiotensin system may have a role in early vascular growth. Studies in tissue culture suggest that both systems could play a role in smooth muscle growth, in conjunction with growth factors such as platelet-derived growth factor (PDGF)-like peptides and endothelin. The early structural change that occurs in hypertension is probably a variant of normal development of the resistance vasculature, with greater secretion of 'normal' growth factors and/or enhanced responsiveness of the vascular smooth muscle.
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PMID:Resistance control in hypertension. 268 90

Accumulating mainly experimental evidence from research of the last 3 decades shows that many types of arterial wall injury can accelerate and intensify the development of atherosclerosis in arteries exposed to chronic hyperlipemia by increasing the permeability of their endothelium for plasma lipoproteins, proteins and several types of smooth muscle mitogens (including soluble platelet-derived growth factor). Of the numerous artery-injuring agents studied experimentally today only those that can be proven to operate in humans at concentrations and durations of action that injure animal arteries can be accepted as capable of playing a role in human atherogenesis. Seven such groups of agents can be recognized at present: blood turbulence, hypertension, certain viruses, metabolic disturbances (including hyperlipemia), certain immune insults, exogenous chemicals, and obstruction of adventitial lymphatics. Most of the above agents cause various degenerative changes in individual endothelial cells or open interendothelial junctions, and they seem to promote the penetration of plasma macromolecules into the wall in 3 different ways: directly through the altered endothelial cytoplasm, through opened interendothelial junctions or through transport in the cytoplasm of immigrating monocytes. None of the commonly occurring injury agents produce complete endothelial denudation of wide areas of the arterial cylinders. New findings from the transmission electron microscopic study of step-serial sections of human arteries obtained under conditions minimizing artificial endothelial loss indicate that endothelial denudation accompanied by platelet adherence and aggregation does not occur over early myoproliferative lesions but occasionally develops over small areas of advanced plaques with mostly necrotic or damaged caps and is, therefore, not an initiating event but a late complication of atherosclerosis. Light microscopic serial section studies of human thrombosed vessels in several centers reveal that thrombogenesis in most human atherosclerotic arteries is initiated by a severe structural injury of the cap of advanced plaques that leads to a microscopic break of the plaque surface through which some blood can enter the plaque interior before it is sealed by a thrombus.
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PMID:The role of arterial wall injury in atherogenesis and arterial thrombogenesis. 268 99


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