scholarly journals The dopamine receptor D4 regulates the proliferation of pulmonary arteries smooth muscle in broilers by downregulating AT1R

2021 ◽  
Vol 1 (1) ◽  
Author(s):  
Xiaoqi Yang ◽  
Yang Fu ◽  
Lianfeng Wu ◽  
Antong Li ◽  
Luyao Ji ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Pulmonary Artery ◽  
Vascular Smooth Muscle ◽  
Fresh Water ◽  
Vascular Remodeling ◽  
At1 Receptor ◽  
Deionized Water ◽  
Ang Ii ◽  
Dopamine Receptor D4

AbstractThe major cause of pulmonary vascular remodeling in broilers is abnormal proliferation of vascular smooth muscle cells (VSMCs), and one of the main causes of pulmonary hypertension syndrome (PHS) in broilers is pulmonary artery vascular remodeling. Forty Arbor Acres (AA) broilers were randomly divided into four groups (n = 10): a control group (deionized water, 0 g/L NaCl), a freshwater group (FW, deionized water + 1 g/L NaCl), highly salinized freshwater group 1 (H-SFW-1, deionized water + 2.5 g/L NaCl) and highly salinized freshwater group 2 (H-SFW-2, deionized water + 5 g/L NaCl). The results of in vivo experiments showed that vascular smooth muscle of the broilers could be significantly proliferated by intake of high-salinity fresh water (H-SFW-1 & H-SFW-2), which significantly increased the content of angiotensin II (Ang II) and the expression of angiotensin II type 1 (AT1) receptor protein. Meanwhile, it significantly decreased the expression of dopamine receptor D4 (DRD4) protein. The results of in vitro experiments showed that exogenous Ang II induced the proliferation of primary VSMCs in broilers, which could be significantly inhibited by DRD4 agonists (D4A, HY-101384A) and enhanced by DRD4 inhibitors (D4I, HY-B0965). In addition, the results of immunoblotting and fluorescence quantitative PCR showed that AT1 receptors could be negatively regulated by DRD4 in VSMCs of broilers, either at the transcriptional or translational level. At the same time, the expression of AT1 receptor could be increased by DRD4 inhibition by D4I and decreased by DRD4 activation by D4A. The negative regulatory effect of DRD4 on AT1 receptor occurred in a dose-dependent manner. These results indicate that long-term intake of highly salinized fresh water can cause PHS in broilers, accompanied by varying degrees of proliferation of pulmonary artery smooth muscle. This mechanism may involve response of its receptor being induced by increased Ang II, while DRD4 can negatively regulate it.

scholarly journals Angiotensin II stimulates phosphorylation of an ectodomain-truncated platelet-derived growth factor receptor-β and its binding to class IA PI3K in vascular smooth muscle cells

2006 ◽  
Vol 397 (2) ◽  
pp. 337-344 ◽  
Author(s):  
Ben-Bo Gao ◽  
Hans Hansen ◽  
Hong-Chi Chen ◽  
Edward P. Feener
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Growth Factor ◽  
Vascular Smooth Muscle ◽  
Growth Factor Receptor ◽  
At1 Receptor ◽  
Dominant Negative ◽  
Platelet Derived Growth Factor ◽  
Ang Ii ◽  
Stimulation Of

PI3K (phosphoinositide 3-kinase) activity is involved in Ang (angiotensin) II-stimulated VSMC (vascular smooth muscle cell) growth and hypertrophy. In the present study, we demonstrate that the inhibition of PI3K in VSMCs by expression of a dominant-negative p85α mutant lacking the p110-binding domain (Δp85), or by treatment of cells with LY294002, inhibited Ang II-stimulated PAI-1 (plasminogen activator inhibitor-1) mRNA expression. Using a GST (glutathione S-transferase) fusion protein containing the p85 N-terminal SH2 (Src homology 2) domain as ‘bait’ followed by MS/MS (tandem MS), we identified a 70 kDa fragment of the p70 PDGFR-β (platelet-derived growth factor receptor-β) as a signalling adapter that is phosphorylated and recruits the p85 subunit of PI3K after Ang II stimulation of AT1 (Ang II subtype 1) receptors on VSMCs. This fragment of the PDGFR-β, which has a truncation of its extracellular domain, accounted for approx. 15% of the total PDGFR-β detected in VSMCs with an antibody against its cytoplasmic domain. Stimulation of VSMCs with Ang II increased tyrosine-phosphorylation of p70 PDGFR-β at Tyr751 and Tyr1021 and increased its binding to p85. PDGF also induced phosphorylation of p70 PDGFR-β, a response inhibited by the PDGF tyrosine kinase selective inhibitor, AG1296. By contrast, Ang II-induced phosphorylation of the 70 kDa receptor was not affected by AG1296. Ang II-stimulated phosphorylation of the p70 PDGFR-β was blocked by the AT1 receptor antagonist, candesartan (CV 11974) and was partially inhibited by PP2 {4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine}, an Src family kinase inhibitor. Our result suggests that the p70 PDGFR-β functions as an adapter that recruits PI3K to the membrane upon AT1 receptor stimulation.

Angiotensin II modulates frizzled-2 receptor expression in rat vascular smooth muscle cells

2005 ◽  
Vol 108 (6) ◽  
pp. 523-530 ◽  
Author(s):  
Giovanna CASTOLDI ◽  
Serena REDAELLI ◽  
Willy M. M. van de GREEF ◽  
Cira R. T. di GIOIA ◽  
Giuseppe BUSCA ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Ang Ii ◽  
Aortic Smooth Muscle

Ang II (angiotensin II) has multiple effects on vascular smooth muscle cells through the modulation of different classes of genes. Using the mRNA differential-display method to investigate gene expression in rat aortic smooth muscle cells in culture in response to 3 h of Ang II stimulation, we observed that Ang II down-regulated the expression of a member of the family of transmembrane receptors for Wnt proteins that was identified as Fzd2 [Fzd (frizzled)-2 receptor]. Fzds are a class of highly conserved genes playing a fundamental role in the developmental processes. In vitro, time course experiments demonstrated that Ang II induced a significant increase (P<0.05) in Fzd2 expression after 30 min, whereas it caused a significant decrease (P<0.05) in Fzd2 expression at 3 h. A similar rapid up-regulation after Ang II stimulation for 30 min was evident for TGFβ1 (transforming growth factor β1; P<0.05). To investigate whether Ang II also modulated Fzd2 expression in vivo, exogenous Ang II was administered to Sprague–Dawley rats (200 ng·kg−1 of body weight·min−1; subcutaneously) for 1 and 4 weeks. Control rats received normal saline. After treatment, systolic blood pressure was significantly higher (P<0.01), whereas plasma renin activity was suppressed (P<0.01) in Ang II- compared with the saline-treated rats. Ang II administration for 1 week did not modify Fzd2 expression in aorta of Ang II-treated rats, whereas Ang II administration for 4 weeks increased Fzd2 mRNA expression (P<0.05) in the tunica media of the aorta, resulting in a positive immunostaining for fibronectin at this time point. In conclusion, our data demonstrate that Ang II modulates Fzd2 expression in aortic smooth muscle cells both in vitro and in vivo.

scholarly journals Angiotensin II, Hypercholesterolemia, and Vascular Smooth Muscle Cells: A Perfect Trio for Vascular Pathology

2020 ◽  
Vol 21 (12) ◽  
pp. 4525
Author(s):  
Amanda St. Paul ◽  
Cali B. Corbett ◽  
Rachael Okune ◽  
Michael V. Autieri
Keyword(s):  
Blood Pressure ◽  
Cardiovascular Disease ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
Vascular Diseases ◽  
Reduce Blood Pressure ◽  
Vascular Pathology ◽  
Lipid Lowering ◽  
Ang Ii

Cardiovascular disease is the leading cause of morbidity and mortality in the Western and developing world, and the incidence of cardiovascular disease is increasing with the longer lifespan afforded by our modern lifestyle. Vascular diseases including coronary heart disease, high blood pressure, and stroke comprise the majority of cardiovascular diseases, and therefore represent a significant medical and socioeconomic burden on our society. It may not be surprising that these conditions overlap and potentiate each other when we consider the many cellular and molecular similarities between them. These intersecting points are manifested in clinical studies in which lipid lowering therapies reduce blood pressure, and anti-hypertensive medications reduce atherosclerotic plaque. At the molecular level, the vascular smooth muscle cell (VSMC) is the target, integrator, and effector cell of both atherogenic and the major effector protein of the hypertensive signal Angiotensin II (Ang II). Together, these signals can potentiate each other and prime the artery and exacerbate hypertension and atherosclerosis. Therefore, VSMCs are the fulcrum in progression of these diseases and, therefore, understanding the effects of atherogenic stimuli and Ang II on the VSMC is key to understanding and treating atherosclerosis and hypertension. In this review, we will examine studies in which hypertension and atherosclerosis intersect on the VSMC, and illustrate common pathways between these two diseases and vascular aging.

K depletion alters angiotensin II receptor expression in vascular smooth muscle cells

1990 ◽  
Vol 258 (5) ◽  
pp. C849-C854 ◽  
Author(s):  
S. L. Linas ◽  
R. Marzec-Calvert ◽  
M. E. Ullian
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Receptor Expression ◽  
Ang Ii ◽  
Surface Receptors ◽  
K Depletion

Dietary K depletion (KD) results in increases in the number of angiotensin II (ANG II) receptors and prevents ANG II-induced downregulation of ANG II receptors in membrane preparations of vessels from KD animals. Because dietary KD results in changes in factors other than K, we K depleted vascular smooth muscle cells (VSMC) in culture to determine the specific effects of KD on ANG II receptor expression and processing. Scatchard analysis of ANG II uptake at 4 degrees C revealed that the number of surface receptors was increased by 37% in cells in which K had been reduced by 45%. This increase also occurred in the presence of cycloheximide. To determine the effect of KD on receptor processing, we measured the number of surface receptors after exposure to ANG II in concentrations sufficient to cause down-regulation. After 30-min exposure to ANG II, the number of surface receptors was reduced by 63% in control cells but only 33% in KD cells. Thirty minutes after withdrawing ANG II, surface binding returned to basal levels in control cells but was still reduced by 20% in KD cells. To determine the functional significance of impaired receptor processing, we measured ANG II uptake at 21 degrees C. Uptake at 21 degrees C depends on the functional number of receptors, i.e., the absolute number of surface receptors and the rate at which receptors are recycled to the surface after ANG II binding. ANG II uptake at 21 degrees C was reduced by 50% in KD cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Bradykinin and angiotensin II: activation of protein kinase C in arterial smooth muscle

1994 ◽  
Vol 266 (5) ◽  
pp. C1406-C1420 ◽  
Author(s):  
B. S. Dixon ◽  
R. V. Sharma ◽  
T. Dickerson ◽  
J. Fortune
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase C ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Ang Ii ◽  
Kinase C ◽  
Membrane Bound

The effects of bradykinin (BK) and angiotensin II (ANG II) were compared in cultured rat mesenteric arterial smooth muscle cells. BK and ANG II activated a phosphoinositide-specific phospholipase C, leading to the rapid release of [3H]inositol phosphates, an increase in intracellular calcium, and formation of sn-1,2-diacylglycerol (DAG). DAG formation was biphasic with a transient peak at 5 s followed by a sustained increase from 60 to 600 s. The BK-mediated increases in inositol triphosphate and DAG were dose dependent with half-maximal increases at concentrations of 5 and 2 nM, respectively. Both hormones were found to activate protein kinase C (PKC) as assessed by phosphorylation of the 68- to 72-kDa intracellular PKC substrate myristoylated alanine-rich C kinase substrate. However, despite similar phosphorylation of this substrate, only ANG II produced a significant increase in membrane-bound PKC activity. The mechanism accounting for the inability of BK to increase membrane-bound PKC activity is unclear. Our studies excluded differential translocation of PKC to the nuclear membrane, production of an inhibitor of membrane-bound PKC activity, and expression of BK and ANG II receptors on different cells as the mechanism. Vascular smooth muscle cells were found to express at least four different PKC isozymes: alpha, delta, zeta, and a faint band for epsilon. All of the isozymes except zeta-PKC were translocated by treatment with the phorbol ester 4 beta-phorbol 12-myristate 13-acetate. However, neither ANG II nor BK produced significant translocation of any measured isozyme; therefore, we could not exclude the possibility that ANG II and BK activate different isozymes of PKC. Both hormones were found to have a similar small and inconsistent effect in stimulating [3H]thymidine incorporation. These observations demonstrate that BK and ANG II have similar biochemical effects on vascular smooth muscle cells and imply that, in selected vessels, the vasodilatory effects of BK mediated by the endothelium may be partially counterbalanced by a vasoconstrictor effect on the underlying vascular smooth muscle cells.

Angiotensin II-induced hypertrophy is potentiated in mice overexpressing p22phox in vascular smooth muscle

2005 ◽  
Vol 288 (1) ◽  
pp. H37-H42 ◽  
Author(s):  
David S. Weber ◽  
Petra Rocic ◽  
Adamantios M. Mellis ◽  
Karine Laude ◽  
Alicia N. Lyle ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
In Vivo Model ◽  
Ros Generation ◽  
Ang Ii ◽  
Vascular Hypertrophy ◽  
Wall Area

Increased reactive oxygen species (ROS) are implicated in several vascular pathologies associated with vascular smooth muscle hypertrophy. In the current studies, we utilized transgenic (Tg) mice (Tg p22smc) that overexpress the p22 phox subunit of NAD(P)H oxidase selectively in smooth muscle. These mice have a twofold increase in aortic p22 phox expression and H2O2 production and thus provide an excellent in vivo model in which to assess the effects of increased ROS generation on vascular smooth muscle cell (VSMC) function. We tested the hypothesis that overexpression of VSMC p22 phox potentiates angiotensin II (ANG II)-induced vascular hypertrophy. Male Tg p22smc mice and negative littermate controls were infused with either ANG II or saline for 13 days. Baseline blood pressure was not different between control and Tg p22smc mice. ANG II significantly increased blood pressure in both groups, with this increase being slightly exacerbated in the Tg p22smc mice. Baseline aortic wall thickness and cross-sectional wall area were not different between control and Tg p22smc mice. Importantly, the ANG II-induced increase in both parameters was significantly greater in the Tg p22smc mice compared with control mice. To confirm that this potentiation of vascular hypertrophy was due to increased ROS levels, additional groups of mice were coinfused with ebselen. This treatment prevented the exacerbation of hypertrophy in Tg p22smc mice receiving ANG II. These data suggest that although increased availability of NAD(P)H oxidase-derived ROS is not a sufficient stimulus for hypertrophy, it does potentiate ANG II-induced vascular hypertrophy, making ROS an excellent target for intervention aimed at reducing medial thickening in vivo.

scholarly journals cAMP attenuates angiotensin-II-induced Egr-1 expression via PKA-dependent signaling pathway in vascular smooth muscle cells

2017 ◽  
Vol 95 (8) ◽  
pp. 928-937 ◽  
Author(s):  
Estelle R. Simo-Cheyou ◽  
Viktoria Youreva ◽  
Ashok K. Srivastava
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
Camp Response Element Binding ◽  
Ang Ii ◽  
Camp Response Element ◽  
Erk Phosphorylation ◽  
Vasp Phosphorylation ◽  
Element Binding Protein ◽  
Dose Dependent Fashion

cAMP has been shown to inhibit vascular smooth muscle cell proliferation and exerts a vasculoprotective effect. An upregulation of the early growth response protein-1 (Egr-1) expression has been linked with the development of atherosclerosis and intimal hyperplasia. We have recently demonstrated that angiotensin-II (Ang-II) stimulates Egr-1 expression via Ca2+/ERK-mediated cAMP-response element binding protein (CREB) activation. However, whether Ang-II-induced signaling leading to Egr-1 expression is modulated by cAMP remains unexplored. Therefore, in the present studies, we have examined the effect of cAMP on Ang-II-induced expression of Egr-1 and associated signaling pathways. Isoproterenol (ISO) and forskolin (FSK) attenuated Ang-II-induced Egr-1 expression in a dose-dependent fashion. In addition, dibutyryl-cAMP and benzoyl-cAMP, as well as isobutylmethylxanthine, attenuated Ang-II-induced Egr-1 expression. Moreover, inhibition of Ang-II-induced Egr-1 expression was accompanied by an increase in the phosphorylation of the vasodilator-activated phosphoprotein (VASP), and this was associated with a concomitant decrease in ERK phosphorylation. Blockade of PKA using H89 decreased VASP phosphorylation, restored Ang-II-induced ERK phosphorylation, and abolished ISO- and FSK-mediated inhibition of Ang-II-induced Egr-1 expression. In summary, these results suggest that PKA-mediated suppression of Ang-II-induced Egr-1 expression and phosphorylation of ERK may be among the mechanisms by which cAMP exerts its vasculoprotective effects.

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