scholarly journals Heart and lung VEGF mRNA expression in rats with monocrotaline- or hypoxia-induced pulmonary hypertension

1998 ◽  
Vol 275 (6) ◽  
pp. H1948-H1956 ◽  
Author(s):  
Chohreh Partovian ◽  
Serge Adnot ◽  
Saadia Eddahibi ◽  
Emmanuel Teiger ◽  
Micheline Levame ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Mrna Expression ◽  
Vascular Remodeling ◽  
Prolonged Exposure ◽  
Similar Degree ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Pulmonary Vascular Remodeling ◽  
The Right ◽  
Vegf Mrna Expression

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen that is upregulated during exposure to hypoxia. In this study, we analyzed heart and lung VEGF mRNA expression and examined pulmonary vascular remodeling as well as myocardial capillary density in two rat models of pulmonary hypertension involving exposure to chronic hypoxia (CH) and treatment with monocrotaline (MCT), respectively. The rats were studied after 0.5, 1, 3, 15, and 30 days of exposure to 10% O2 or 1, 6, and 30 days after a subcutaneous MCT injection (60 mg/kg). Both CH and MCT induced pulmonary hypertension and hypertrophy of the right ventricle (RV) with increased RV weight and atrial natriuretic peptide mRNA expression. VEGF mRNA expression as assessed by Northern blot analysis was potently induced after 12 h of hypoxia in both the right and left ventricles. After prolonged exposure to hypoxia, VEGF mRNA returned to baseline in the left ventricle (LV) but remained increased in the RV, where it peaked after 30 days. In MCT rats, VEGF mRNA was unchanged in the LV but decreased by 50% in the RV and by 90% in the lungs after 30 days. VEGF mRNA remained unchanged in the lungs from CH rats. Pulmonary vascular remodeling was more pronounced in MCT than in CH rats. The number of capillaries per RV myocyte was increased in rats exposed to 30 days of hypoxia, whereas it remained unchanged in MCT rats despite a similar degree of RV hypertrophy. Our results suggest that the sustained increase in VEGF expression in the hypertrophied RV during CH may account for the increased number of capillaries per myocyte. In contrast, reduced VEGF expression in the lungs and RV of MCT rats may aggravate pulmonary vascular remodeling and compromise RV myocardial perfusion.

scholarly journals Adenosine upregulates VEGF expression in cultured myocardial vascular smooth muscle cells

1999 ◽  
Vol 277 (2) ◽  
pp. H595-H602 ◽  
Author(s):  
Jian-Wei Gu ◽  
Ann L. Brady ◽  
Vivek Anand ◽  
Michael C. Moore ◽  
Whitney C. Kelly ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Mrna Expression ◽  
Vascular Smooth Muscle Cells ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Protein Levels ◽  
Hypoxic Conditions ◽  
Vegf Mrna Expression ◽  
Vegf Protein

We tested whether adenosine has differential effects on vascular endothelial growth factor (VEGF) expression under normoxic and hypoxic conditions, and whether A1 or A2 receptors (A1R; A2R) mediate these effects. Myocardial vascular smooth muscle cells (MVSMCs) from dog coronary artery were exposed to hypoxia (1% O2) or normoxia (20% O2) in the absence and presence of adenosine agonists or antagonists for 18 h. VEGF protein levels were measured in media with ELISA. VEGF mRNA expression was determined with Northern blot analysis. Under normoxic conditions, the adenosine A1R agonists, N 6-cyclopentyladenosine and R(-)- N 6-(2-phenylisopropyl)adenosine did not increase VEGF protein levels at A1R stimulatory concentrations. However, adenosine (5 μM) and the adenosine A2R agonist N 6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)]ethyl adenosine (DPMA; 100 nM) increased VEGF protein levels by 51 and 132% and increased VEGF mRNA expression by 44 and 90%, respectively, in cultured MVSMCs under normoxic conditions. Hypoxia caused an approximately fourfold increase in VEGF protein and mRNA expression, which could not be augmented with exogenous adenosine, A2R agonist (DPMA), or A1R agonist [1,3-diethyl-8-phenylxanthine (DPX)]. The A2R antagonist 8-(3-chlorostyryl)-caffeine completely blocked adenosine-induced VEGF protein and mRNA expression and decreased baseline VEGF protein levels by up to ∼60% under normoxic conditions but only by ∼25% under hypoxic conditions. The A1R antagonist DPX had no effect. These results are consistent with the hypothesis that 1) adenosine increases VEGF protein and mRNA expression by way of A2R. 2) Adenosine plays a major role as an autocrine factor regulating VEGF expression during normoxic conditions but has a relatively minor role during hypoxic conditions. 3) Endogenous adenosine can account for the majority of basal VEGF secretion by MVSMCs under normoxic conditions and could therefore be a maintenance factor for the vasculature.

Matrix Metalloproteinase-3 Enhances the Free Fatty Acids-Induced VEGF Expression in Adipocytes Through Toll-Like Receptor 2

2008 ◽  
Vol 233 (10) ◽  
pp. 1213-1221 ◽  
Author(s):  
Toru Kawamura ◽  
Kentaro Murakami ◽  
Hideaki Bujo ◽  
Hiroyuki Unoki ◽  
Meizi Jiang ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Matrix Metalloproteinase ◽  
Mrna Expression ◽  
Visceral Fat ◽  
Neutralizing Antibody ◽  
Toll Like Receptor ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Tlr2 Expression ◽  
Vegf Mrna Expression

Infiltrated macrophages (Mϕ) are believed to cause pathological changes in the surrounding adipocytes through the secretion of active molecules in visceral fat. Matrix metalloproteinase (MMP)-3 is secreted from Mϕ, and enhances expression of the inflammatory cytokines through the activation of toll-like receptor (TLR) 2. Visceral adipocytes express high levels of vascular endothelial growth factor (VEGF), and the degree of visceral fat accumulation is associated with the plasma VEGF concentration in obese subjects. The aim of the study is to clarify the role of MMP-3 in the enhancement of the free fatty acids (FFAs)-induced VEGF expression through TLR2 in visceral adipocytes. One mM FFAs induced VEGF mRNA and protein expression in 3T3-L1 adipocytes. The FFAs-induced VEGF expression was mostly mediated by TLR2. A high fat intake increased the VEGF mRNA expression in visceral fat and the VEGF concentration in plasma, accompanied with the increase in the plasma FFAs concentration in mice. These increases were largely inhibited in TLR2-deficient mice. The FFAs-induced VEGF expression was increased in the presence of Mϕ-conditioned medium (CM) in adipocytes, and the enhancement was inhibited by a MMP-3 inhibitor or a neutralizing antibody against MMP-3. The active form of MMP-3 induced the VEGF mRNA expression, as well as TLR2, in adipocytes. The increase in the VEGF expression by MMP-3 was inhibited by the treatment with siRNA for TLR2. The enhancement of FFAs-induced TLR2 expression by Mϕ-CM was inhibited by blocking of the MMP-3. The increase in the VEGF mRNA expression by Mϕ-CM or MMP-3 was partially inhibited by a neutralizing antibody against TNF-α. These results indicate that MMP-3 in Mϕ-CM enhances the FFAs-induced VEGF expression in adipocytes through the increase in the TLR2 expression. The MMP-3 secreted from the infiltrated Mϕ may be a regulator of the VEGF expression in visceral adipocytes.

scholarly journals Statins Augment Vascular Endothelial Growth Factor Expression in Osteoblastic Cells via Inhibition of Protein Prenylation

Endocrinology ◽  
2003 ◽  
Vol 144 (2) ◽  
pp. 681-692 ◽  
Author(s):  
Toyonobu Maeda ◽  
Tetsuya Kawane ◽  
Noboru Horiuchi
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Mrna Expression ◽  
Osteoblastic Cells ◽  
Vascular Endothelial ◽  
Protein Prenylation ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Endothelial Growth Factor ◽  
Vegf Mrna Expression

Statins such as simvastatin are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that inhibit cholesterol synthesis. We presently investigated statin effects on vascular endothelial growth factor (VEGF) expression in osteoblastic cells. Hydrophobic statins including simvastatin, atorvastatin, and cerivastatin–but not a hydrophilic statin, pravastatin–markedly increased VEGF mRNA abundance in nontransformed osteoblastic cells (MC3T3-E1). Simvastatin (10−6m) time-dependently augmented VEGF mRNA expression in MC3T3-E1 cells, mouse stromal cells (ST2), and rat osteosarcoma cells (UMR-106). According to heterogeneous nuclear RNA and Northern analyses, 10−6m simvastatin stimulated gene expression for VEGF in MC3T3-E1 cells without altering mRNA stability. Transcriptional activation of a VEGF promoter-luciferase construct (−1128 to +827), significantly increased by simvastatin administration. As demonstrated by gel mobility shift assay, simvastatin markedly enhanced the binding of hypoxia-responsive element-protein complexes. These results indicate that the stimulation of the VEGF gene by simvastatin in MC3T3-E1 cells is transcriptional in nature. VEGF secretion into medium was increased in MC3T3-E1 by 10−6m simvastatin. Pretreating MC3T3-E1 cells with mevalonate or geranylgeranyl pyrophosphate, a mevalonate metabolite, abolished simvastatin-induced VEGF mRNA expression; manumycin A, a protein prenylation inhibitor, mimicked statin effects on VEGF expression. The effect of simvastatin was blocked by pretreatment with wortmannin and LY294002, specific phosphatidylinositide-3 kinase inhibitors. Simvastatin enhanced mineralized nodule formation in culture, whereas coincubation with mevalonate, geranylgeranyl pyrophosphate, LY294002, or VEGF receptor 2 inhibitor (SU1498) abrogated statin-induced mineralization. Thus, statins stimulate VEGF expression in osteoblasts via reduced protein prenylation and the phosphatidylinositide-3 kinase pathway, promoting osteoblastic differentiation.

scholarly journals ERK5 Contributes to VEGF Alteration in Diabetic Retinopathy

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Yuexiu Wu ◽  
Yufeng Zuo ◽  
Rana Chakrabarti ◽  
Biao Feng ◽  
Shali Chen ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Mrna Expression ◽  
Diabetic Rats ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Vasoactive Factors ◽  
Extracellular Signal ◽  
Common Causes ◽  
Endothelial Growth Factor ◽  
Vegf Mrna Expression

Diabetic retinopathy is one of the most common causes of blindness in North America. Several signaling mechanisms are activated secondary to hyperglycemia in diabetes, leading to activation of vasoactive factors. We investigated a novel pathway, namely extracellular signal regulated kinase 5 (ERK5) mediated signaling, in modulating glucose-induced vascular endothelial growth factor (VEGF) expression. Human microvascular endothelial cells (HMVEC) were exposed to glucose. In parallel, retinal tissues from streptozotocin-induced diabetic rats were examined after 4 months of follow-up. In HMVECs, glucose caused initial activation followed by deactivation of ERK5 and its downstream mediators myocyte enhancing factor 2C (MEF2C) and Kruppel-like factor 2 (KLF2) mRNA expression. ERK5 inactivation further led to augmented VEGF mRNA expression. Furthermore, siRNA mediated ERK5 gene knockdown suppressed MEF2C and KLF2 expression and increased VEGF expression and angiogenesis. On the other hand, constitutively active MEK5, an activator of ERK5, increased ERK5 activation and ERK5 and KLF2 mRNA expression and attenuated basal- and glucose-induced VEGF mRNA expression. In the retina of diabetic rats, depletion of ERK5, KLF2 and upregulation of VEGF mRNA were demonstrated. These results indicated that ERK5 depletion contributes to glucose induced increased VEGF production and angiogenesis. Hence, ERK5 may be a putative therapeutic target to modulate VEGF expression in diabetic retinopathy.

Metalloproteinase inhibition by Batimastat attenuates pulmonary hypertension in chronically hypoxic rats

2003 ◽  
Vol 285 (1) ◽  
pp. L199-L208 ◽  
Author(s):  
Jan Herget ◽  
Jana Novotná ◽  
Jana Bíbová ◽  
Viera Povýšilová ◽  
Marie Vaňková ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Causative Factor ◽  
Systemic Arterial Pressure ◽  
Collagenolytic Activity ◽  
Pulmonary Vascular Remodeling ◽  
Arterial Blood ◽  
Fraction Of Inspired Oxygen ◽  
Lung Vessels

Chronic hypoxia induces lung vascular remodeling, which results in pulmonary hypertension. We hypothesized that a previously found increase in collagenolytic activity of matrix metalloproteinases during hypoxia promotes pulmonary vascular remodeling and hypertension. To test this hypothesis, we exposed rats to hypoxia (fraction of inspired oxygen = 0.1, 3 wk) and treated them with a metalloproteinase inhibitor, Batimastat (30 mg/kg body wt, daily ip injection). Hypoxia-induced increases in concentration of collagen breakdown products and in collagenolytic activity in pulmonary vessels were inhibited by Batimastat, attesting to the effectiveness of Batimastat administration. Batimastat markedly reduced hypoxic pulmonary hypertension: pulmonary arterial blood pressure was 32 ± 3 mmHg in hypoxic controls, 24 ± 1 mmHg in Batimastat-treated hypoxic rats, and 16 ± 1 mmHg in normoxic controls. Right ventricular hypertrophy and muscularization of peripheral lung vessels were also diminished. Batimastat had no influence on systemic arterial pressure or cardiac output and was without any effect in rats kept in normoxia. We conclude that stimulation of collagenolytic activity in chronic hypoxia is a substantial causative factor in the pathogenesis of pulmonary vascular remodeling and hypertension.

scholarly journals The role of inflammation in hypoxic pulmonary hypertension: from cellular mechanisms to clinical phenotypes

2015 ◽  
Vol 308 (3) ◽  
pp. L229-L252 ◽  
Author(s):  
Steven C. Pugliese ◽  
Jens M. Poth ◽  
Mehdi A. Fini ◽  
Andrea Olschewski ◽  
Karim C. El Kasmi ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Signaling Pathways ◽  
Vascular Remodeling ◽  
Mesenchymal Cells ◽  
World Health ◽  
Small Subset ◽  
Cellular Interactions ◽  
Pulmonary Vascular Remodeling ◽  
Hypoxic Pulmonary Hypertension ◽  
Group I

Hypoxic pulmonary hypertension (PH) comprises a heterogeneous group of diseases sharing the common feature of chronic hypoxia-induced pulmonary vascular remodeling. The disease is usually characterized by mild to moderate pulmonary vascular remodeling that is largely thought to be reversible compared with the progressive irreversible disease seen in World Health Organization (WHO) group I disease. However, in these patients, the presence of PH significantly worsens morbidity and mortality. In addition, a small subset of patients with hypoxic PH develop “out-of-proportion” severe pulmonary hypertension characterized by pulmonary vascular remodeling that is irreversible and similar to that in WHO group I disease. In all cases of hypoxia-related vascular remodeling and PH, inflammation, particularly persistent inflammation, is thought to play a role. This review focuses on the effects of hypoxia on pulmonary vascular cells and the signaling pathways involved in the initiation and perpetuation of vascular inflammation, especially as they relate to vascular remodeling and transition to chronic irreversible PH. We hypothesize that the combination of hypoxia and local tissue factors/cytokines (“second hit”) antagonizes tissue homeostatic cellular interactions between mesenchymal cells (fibroblasts and/or smooth muscle cells) and macrophages and arrests these cells in an epigenetically locked and permanently activated proremodeling and proinflammatory phenotype. This aberrant cellular cross-talk between mesenchymal cells and macrophages promotes transition to chronic nonresolving inflammation and vascular remodeling, perpetuating PH. A better understanding of these signaling pathways may lead to the development of specific therapeutic targets, as none are currently available for WHO group III disease.

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