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

Hemodynamic factors, circulating hormones, paracrine factors, and intracrine factors influence vascular smooth muscle growth and plasticity. The well-characterized role of angiotensin II in the modulation of vascular tone and cell function may be critically involved in the mechanisms by which vascular smooth muscle responds to signals associated with vascular endothelial dysfunction and increases in oxidative stress. Studies from this laboratory suggest that the trophic actions of angiotensin II may be intrinsically regulated by angiotensin-(1-7), a separate product of the angiotensin system derived from the common substrate, angiotensin I. Exposure of cultured vascular smooth muscle cells to angiotensin-(1-7) inhibited the trophic actions of angiotensin II and reduced the expression of the mitogenic effects of both normal serum and platelet-derived growth factor. The growth-inhibitory actions of angiotensin-(1-7) were blocked by the selective D-alanine(7)-angiotensin-(1-7) antagonist and the nonselective angiotensin receptor blocker sarcosine(1)-threonine(8)-angiotensin II. In contrast, subtype-selective antagonists for the AT(1) and AT(2) receptors had no effect on the inhibitory actions of angiotensin-(1-7), a finding that is consistent with the pharmacological characterization of a high-affinity (125)I-labeled angiotensin-(1-7) binding site in the vasculature by use of selective and nonselective angiotensin II receptor antagonists. The relevance of these findings to the proliferative response of vascular smooth muscle cells after endothelial injury was confirmed by assessment of the effect of a 12-day infusion of angiotensin-(1-7) on neointimal formation. In these experiments, the proliferative response produced by injuring the carotid artery was inhibited by angiotensin-(1-7) through a mechanism that could not be explained by changes in arterial pressure. Because plasma angiotensin-(1-7) increased to levels comparable to those found in animals and human subjects given therapeutic doses of angiotensin-converting enzyme inhibitors, angiotensin-(1-7) may be one factor participating in the reversal of vascular proliferation during inhibition of angiotensin II formation or activity.
Hypertension 1999 Oct
PMID:State-of-the-Art lecture. Antiproliferative actions of angiotensin-(1-7) in vascular smooth muscle. 1052 90

We have previously shown, in a neonatal rat cell line, that angiotensin II (Ang II)-induced proliferation in vascular smooth muscle cells is extracellular matrix (ECM) dependent. We hypothesized that such an effect might be mediated via differences in Ang II-induced increases in the transcriptional factor early growth response-1 (Egr-1) gene and, consequently, in platelet-derived growth factor (PDGF). Cultured human newborn aortic smooth muscle cells were studied on 4 different surfaces: (1) plastic, (2) laminin, (3) collagen, and (4) fibronectin. Ang II-induced increases in DNA synthesis were significantly greater on collagen (2.0+/-0.3-fold) and fibronectin (1.9+/-0.3-fold) than on laminin (1.0+/-0.2-fold) or plastic (1.4+/-0.2-fold). As with DNA synthesis, at 48 and 72 hours, Ang II-induced increases in cell numbers occurred only in cells grown on collagen and fibronectin culture plates and were blocked by an antagonist to the angiotensin type 1 (losartan, 10 micromol/L) but not the angiotensin type 2 (PD 123319, 10 micromol/L) receptor. Anti-PDGF AA antibody (6 microg/mL) blocked the increase in DNA synthesis by 60% to 64% in cells on collagen or fibronectin cultures but not on plastic cultures. When PDGF-AA (10 ng/mL) and Ang II were added together, DNA synthesis increased 2-fold and did not differ on the various ECM proteins. Increases in PDGF A-chain mRNA were observed only in cells grown on collagen (3.21+/-0.65-fold) and fibronectin (2.86+/-0.49-fold) plates 2 to 8 hours after the addition of Ang II and were blocked by losartan but not PD 123319. Expression of Egr-1, an early growth response gene, increased at 15 minutes, peaked at 30 minutes, and returned to normal after 2 hours with Ang II treatment. Ang II-induced increases in Egr-1 mRNA were greater on collagen (4. 82+/-0.66-fold at maximum) and fibronectin (4.01+/-0.56-fold) than on laminin (2.74+/-0.45-fold) or plastic (2.53+/-0.40-fold) and were blocked by losartan but not PD 123319. Thus, in human vascular smooth muscle cells in culture, Ang II-induced proliferation is mediated via the angiotensin type 1 receptor, dependent on ECM proteins, and regulated by differential gene expression of Egr-1 and PDGF-1.
Hypertension 1999 Nov
PMID:Matrix-dependent gene expression of egr-1 and PDGF A regulate angiotensin II-induced proliferation in human vascular smooth muscle cells. 1056 96

Although cAMP is an important second messenger that plays a pivotal role in the regulation of platelet aggregation and dilatation of blood vessels, little is known about the action of cAMP on the growth of vascular smooth muscle cells (VSMCs). Thus, we initially studied the effects of cAMP accumulation by using various cAMP stimulants, including a phosphodiesterase type 3 inhibitor (cilostazol) on human aortic VSMC growth. Accumulation of cAMP inhibited the platelet-derived growth factor (PDGF)-stimulated VSMC growth in a dose-dependent manner (P<0.01), whereas PDGF significantly stimulated the growth of human VSMCs. Thus, we focused on the role of cell cycle regulatory genes, especially on a negative regulator, an anti-oncogene, p53. The protein of p53 was potentiated by cilostazol as well as forskolin and 8-bromo-cAMP, whereas PDGF decreased p53 expression. Upregulation of p53 protein by cAMP was further confirmed by the observation that the decrease in p21, a p53-inducible protein, by PDGF was significantly attenuated by cilostazol in a dose-dependent manner (P<0.01). These results revealed that accumulation of cAMP inhibited VSMC proliferation, which was at least in part due to an increase in p53-p21 expression. Because p53 and p21 have been reported to induce apoptosis, we examined apoptotic cells for cAMP accumulation. Incubation of VSMCs with cilostazol resulted in a significant increase in apoptotic cells in a dose-dependent manner compared with vehicle treatment as assessed by nuclear chromatic morphology (P<0.01); forskolin also stimulated apoptotic cells. Consistent with nuclear staining, DNA fragmentation in VSMCs treated with forskolin as well as 8-bromo-cAMP and cilostazol was significantly increased compared with DNA fragmentation in VSMCs treated with vehicle, whereas PDGF significantly decreased the rate of DNA fragmentation (P<0.01). Overall, these results demonstrated that cAMP inhibited the proliferation of human aortic VSMCs, accompanied by p53-p21-mediated apoptosis. Analogues of cAMP that have direct inhibitory effects on VSMC proliferation can be considered as potential antiproliferative drugs against VSMC growth.
Hypertension 2000 Jan
PMID:Cyclic AMP inhibited proliferation of human aortic vascular smooth muscle cells, accompanied by induction of p53 and p21. 1064 4

beta(1)-Integrins play an important role for adhesion and spreading of human smooth muscle cells. In the present study we examined the influence of angiotensin II and platelet-derived growth factor (PDGF)-BB on beta(1)-integrin-dependent functions of human smooth muscle cells obtained from iliac arteries. Treatment of these cells with PDGF-BB (20 ng/mL) and Angiotensin II (1 micromol/L) did not change beta(1)-integrin expression up to 48 hours as analyzed by flow cytometry and reverse transcription polymerase chain reaction. beta(1)-integrins predominantly mediated adhesion of human smooth muscle cells to collagen I (79.7+/-4.4%, P<0.01) and fibronectin (66. 6+/-2.4%, P<0.01). Treatment of smooth muscle cells with Angiotensin II (1 micromol/L) and PDGF-BB (20 ng/mL) significantly increased the adhesion to collagen I by 56.5% and 44.3%, respectively, and to fibronectin by 49.6% and 36.4%, respectively (all P<0.05). Angiotensin II-induced effects were mediated by the AT(1) receptor. The PDGF-BB mediated increase of adhesion was inhibited in the presence of genestein, a tyrosine-kinase inhibitor and by protein kinase C downregulation with phorbol 12-myristate 13-acetate. Spreading of smooth muscle cells also was beta(1)-integrin dependent on collagen I and alpha(5)beta(1)-integrin dependent on fibronectin. Angiotensin II and PDGF-BB increased cell spreading on fibronectin up to 276% and 318%, respectively, and on collagen I up to 133% and 138% (all P<0.05). These increases were significantly inhibited by blocking antibodies against beta(1)-integrin, alpha(5)-integrin on fibronectin, the AT(1) receptor blocker irbesartan, and genestein. The present data demonstrate that angiotensin II and as well PDGF-BB enhance beta(1)-integrin-dependent adhesion and spreading of human vascular smooth muscle cells. Furthermore, the experiments with PDGF suggest an involvement of protein kinase C activation leading to these enhanced effects.
Hypertension 2000 Jan
PMID:Angiotensin II and PDGF-BB stimulate beta(1)-integrin-mediated adhesion and spreading in human VSMCs. 1064 7

To separate the role of ANG II from pressure in hypertrophy of the vascular wall in one-kidney, one-clip (1K1C) hypertension, experimental and sham-operated rats were given the AT(1)-receptor antagonist losartan (20 mg x kg(-1) x day(-1)) or tap water for 14 days. Mean arterial pressure was elevated in both experimental groups compared with controls. Rats were anesthetized with pentobarbital sodium, and the thoracic aorta and carotid, small mesenteric, and external spermatic arteries were harvested and embedded in paraffin. Tissue sections were used for morphological analysis, immunohistochemistry for 5-bromo-2'-deoxyuridine (BrdU) and platelet-derived growth factor (PDGF)-AA, stereological measurements, and in situ hybridization with a (35)S-labeled riboprobe for PDGF-A mRNA. Elevated cross-sectional areas of thoracic, carotid, and small mesenteric artery in 1K1C rats were not reduced by losartan. The internal diameter of the external spermatic artery and microvascular density of the cremaster muscle were reduced in 1K1C rats. The number of BrdU-positive nuclei per cross section did not differ between 1K1C and control arteries. PDGF-A mRNA was elevated in the arterial walls of 1K1C rats compared with controls and was hardly changed by losartan. PDGF-A protein stained strongly in the media of 1K1C arteries and was not inhibited by losartan; it appeared in the adventitia of all aortas and carotid arteries. These observations demonstrate that effects of ANG II mediated through the AT(1) receptor are not necessary for hypertrophy of the vascular wall during 1K1C hypertension or expression of PDGF-A.
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PMID:AT(1) receptor inhibition does not reduce arterial wall hypertrophy or PDGF-A expression in renal hypertension. 1066 94

Previously, it was shown that 5/6 renal mass reduction by surgical excision (RK-NX) results in a marked reduction of glomerulosclerosis (GS) at 6 wk compared with the conventional 5/6 renal ablation by infarction (RK-I) model. To determine the pathogenetic correlates of the striking differences in GS, radiotelemetrically measured BP; single nephron function; glomerular volume; the temporal expression of mRNA for renin, transforming growth factor-beta, and platelet-derived growth factor-B; and plasma renin concentration were compared between RK-NX, RK-I, and sham-operated control rats. Hypertension only developed in the RK-I model, was present at 3 d after infarction, and was correlated with both an increased expression of renin mRNA by Northern analysis and elevated plasma renin concentration. Structural (glomerular volume) and functional (single nephron blood flow and GFR) indices of the compensatory adaptive response were significantly but similarly increased in the RK-NX and RK-I rats compared with sham-operated controls, indicating that these adaptations per se are not responsible for the initiation of GS after 5/6 renal mass reduction. Glomerular capillary pressure (P(GC)) was also significantly increased in both RK-I (56 +/- 2 mmHg) and RK-NX rats (50 +/- 0.9 mmHg) compared with controls (46 +/- 0.8 mmHg, P < 0.01), but the increase was significantly greater in RK-I versus RK-NX rats (P < 0.05) consistent with the higher BP in RK-I rats. These data indicate that differences in renin probably account for the early divergence of BP (and P(GC)) responses between RK-I and RK-NX models. Transforming growth factor-beta and platelet-derived growth factor-B mRNA expression in pooled RNA from kidneys from each group showed increases at 21 d along with early evidence of glomerular injury in the RK-I group but not in the RK-NX group, consistent with their postulated roles as molecular mediators of GS, but only in rats with pathologic glomerular hypertension.
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PMID:Functional and structural correlates of glomerulosclerosis after renal mass reduction in the rat. 1070 73

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.
Hypertension 2000 Mar
PMID:Cardiovascular effects of combination of perindopril, candesartan, and amlodipine in hypertensive rats. 1072 May 93

Spontaneously hypertensive rats (SHR)-derived vascular smooth muscle cells show exaggerated growth and increased expression of platelet-derived growth factor (PDGF) A-chain mRNA. We examined the effect of methylene methylimino linkage of antisense oligodeoxynucleotide, a novel modification of antisense oligodeoxynucleotide designed to increase nuclease resistance, to PDGF A-chain on the exaggerated growth of vascular smooth muscle cells from SHR. Methylene methylimino-linked oligodeoxynucleotide provided complete resistance against S1 nuclease. Methylene methylimino linkage of antisense oligodeoxynucleotide to PDGF A-chain resulted in a rapid inhibition of basal DNA synthesis of vascular smooth muscle cells from SHR. This inhibition was much greater than that produced by phosphorothioate linkage of antisense oligodeoxynucleotide to PDGF A-chain. The methylene methylimino linkage of antisense oligodeoxynucleotide to PDGF A-chain may prove useful in the treatment of arterial proliferative diseases including hypertension.
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PMID:Effect of methylene methylimino linkage of antisense oligonucleotide to the platelet-derived growth factor A-chain on growth of vascular smooth muscle cells from spontaneously hypertensive rats. 1076 64

The effect of potassium on the migration of vascular smooth muscle cells was analyzed in media made with extracellular potassium concentrations of 3, 4, 5, and 6 mmol/L. The migration of cultured porcine coronary artery cells was stimulated with platelet-derived growth factor (PDGF)-BB. In the first study, cells were exposed to PDGF-BB at concentrations of 0, 10, or 20 ng/mL for 5 hours with the use of a Boyden chamber. Cells were quiescent overnight in 0.5% fetal bovine serum in Dulbecco's modified Eagle's medium with an extracellular potassium concentration of 4 mmol/L. With increasing potassium concentration, migration was significantly inhibited (P<0. 02, 2-way ANOVA). In the cells exposed to 10 ng/mL PDGF-BB, migration ranged from 500+/-86% to 294+/-44% (value in wells with 0 ng/mL PDGF-BB and 4 mmol/L potassium concentration=100%) in medium containing 3 to 6 mmol/L extracellular potassium concentration (P<0. 03). Long-term potassium exposure was investigated in cells grown in 5% serum in Dulbecco's modified Eagle's medium with an extracellular potassium concentration of 3, 4, 5, or 6 mmol/L for 3 to 4 weeks. Migration was assessed with 0 or 20 ng/mL PDGF-BB. Migration was significantly inhibited by the elevation of extracellular potassium concentration (P<0.01, 2-way ANOVA). With 20 ng/mL PDGF-BB, the migration rates ranged from 152+/-11% in medium with 3 mmol/L potassium to 69+/-5% in 6 mmol/L potassium (P<0.01). Increases in extracellular potassium concentration within the physiological range significantly and directly inhibit vascular smooth muscle cell migration.
Hypertension 2000 Apr
PMID:Inhibition of vascular smooth muscle cell migration by elevation of extracellular potassium concentration. 1077 67

We recently demonstrated that alpha(v)beta(3) integrins are involved in the mechanisms of angiotensin II (Ang II)-induced DNA synthesis and collagen gel contractions in rat cardiac fibroblasts (CFBs), cellular mechanisms that are relevant for cardiac remodeling. The aim of the present study was to elucidate the effect of Ang II and other growth factors on the regulation of the alpha(v)beta(3) integrins in fibroblasts from neonatal rat hearts. The alpha(v)beta(3) integrin receptor expression was significantly increased (P<0.05) at the mRNA level after treatment with Ang II, transforming growth factor-beta(1) (TGF-beta(1)), and platelet-derived growth factor (PDGF) for 8 and 16 hours. The surface expression of the alpha(v) and beta(3) integrin subunits was elevated after 32 and 48 hours (P<0.05) as determined with flow cytometry. To investigate fibroblast motility, we performed chemotaxis experiments with transwell chambers. Ang II was chemotactic for CFBs, as tested with checkerboard experiments. The chemotactic effect was concentration dependent and was completely blocked by Ang II type 1 receptor blockers but not by Ang II type 2 receptor blocker PD 123319. Ang II- and PDGF-BB-mediated chemotaxis could be significantly inhibited by RGD peptides and the blocking antibodies against alpha(v)beta(3) integrin (both P<0.01). Adhesion of CFBs to vitronectin was partially inhibited by an antibody to alpha(v)beta(3) integrin but was mainly mediated by an alpha(v)beta(5) integrin. Relevant in vivo expression of alpha(v)beta(3) integrin by CFBs was confirmed with in situ hybridization with probes for alpha(v) and beta(3) mRNA in rat hearts. The present study demonstrates that the expression of alpha(v)beta(3) integrin is augmented by Ang II, PDGF, and TGF-beta(1) in neonatal CFBs. Furthermore, this integrin is involved in the chemotaxis, motility, and adhesion of CFBs. The present findings support the current concept that integrins participate in the control of fibroblast behavior during cardiac remodeling mechanisms.
Hypertension 2000 Apr
PMID:Angiotensin II and alpha(v)beta(3) integrin expression in rat neonatal cardiac fibroblasts. 1077 72


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