Evidence for a protective role of placental growth factor in cardiovascular disease

Placental growth factor (PlGF) is a mitogen for endothelial cells, but it can also act as a proinflammatory cytokine. Because it promotes early stages of plaque formation in experimental models of atherosclerosis and was implicated in epidemiological associations with risk of cardiovascular disease (CVD), PlGF has been attributed a pro-atherogenic role. Here, we investigated whether PlGF has a protective role in CVD and whether elevated PlGF reflects activation of repair processes in response to vascular stress. In a population cohort of 4742 individuals with 20 years of follow-up, high baseline plasma PlGF was associated with increased risk of cardiovascular death, myocardial infarction, and stroke, but these associations were lost or weakened when adjusting for cardiovascular risk factors known to cause vascular stress. Exposure of cultured endothelial cells to high glucose, oxidized low-density lipoprotein (LDL) or an inducer of apoptosis enhanced the release of PlGF. Smooth muscle cells and endothelial cells treated with PlGF small interference RNA demonstrated that autocrine PlGF stimulation plays an important role in vascular repair responses. High expression of PlGF in human carotid plaques removed at surgery was associated with a more stable plaque phenotype and a lower risk of future cardiovascular events. When adjusting associations of PlGF with cardiovascular risk in the population cohort for plasma soluble tumor necrosis factor–related apoptosis–inducing ligand (TRAIL) receptor-2, a biomarker of cellular stress, a high PlGF/TRAIL receptor-2 ratio was associated with a lower risk. Our findings provide evidence for a protective role of PlGF in CVD.

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Involvement of miR-30c and miR-301a in immediate induction of plasminogen activator inhibitor-1 by placental growth factor in human pulmonary endothelial cells

Biochemical Journal ◽

10.1042/bj20101585 ◽

2011 ◽

Vol 434 (3) ◽

pp. 473-482 ◽

Cited By ~ 43

Author(s):

Nitin Patel ◽

Stanley M. Tahara ◽

Punam Malik ◽

Vijay K. Kalra

Keyword(s):

Endothelial Cells ◽

Growth Factor ◽

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Placental Growth Factor ◽

Luciferase Reporter ◽

Plasminogen Activator Inhibitor 1 ◽

Activator Inhibitor ◽

Pai 1

PAI-1 (plasminogen activator inhibitor-1) is a key physiological inhibitor of fibrinolysis. Previously, we have reported PlGF (placental growth factor)-mediated transcriptional up-regulation of PAI-1 (SERPINE1) mRNA expression via activation of HIF-1α (hypoxia-inducible factor-1α) and AP-1 (activator protein-1) in HPMVECs (human pulmonary microvascular endothelial cells), which resulted in elevated PAI-1 in humans with SCA (sickle cell anaemia). In the present study, we have identified the role of post-transcriptional mechanism(s) of PlGF-mediated accumulation of PAI-1 mRNA in HPMVECs by examining the role of microRNAs (miRNAs/miRs) in PlGF-induced PAI-1 mRNA stability. Our results show reduced expression of miR-30c and miR-301a, but not of miR-99a, in response to PlGF, which have evolutionarily conserved binding sites in the 3′-UTR (3′-untranslated region) of PAI-1 mRNA. Transfection of anti-miR-30c or anti-miR-301a oligonucleotides resulted in increased PAI-1 mRNA levels, which were increased further with PlGF stimulation. Conversely, overexpression of pre-miR-30c or pre-miR-301a resulted in an attenuation of PlGF-induced PAI-1 mRNA and protein levels. Luciferase reporter assays using wild-type and mutant 3′-UTR constructs confirmed that the PAI-1 3′-UTR is indeed a direct target of miR-30c and miR-301a. Finally, plasma levels of miR-30c and miR-301a were significantly down-regulated in patients with SCA compared with normal controls. These results provide a post-transcriptional regulatory mechanism of PlGF-induced PAI-1 elevation.

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Protective Role of Insulin-Like Growth Factor-1 Receptor in Endothelial Cells against Unilateral Ureteral Obstruction–Induced Renal Fibrosis

American Journal Of Pathology ◽

10.1016/j.ajpath.2015.01.027 ◽

2015 ◽

Vol 185 (5) ◽

pp. 1234-1250 ◽

Cited By ~ 23

Author(s):

Ming Liang ◽

Lauren E. Woodard ◽

Anlin Liang ◽

Jinlong Luo ◽

Matthew H. Wilson ◽

...

Keyword(s):

Endothelial Cells ◽

Growth Factor ◽

Ureteral Obstruction ◽

Renal Fibrosis ◽

Protective Role ◽

Unilateral Ureteral Obstruction ◽

Insulin Like Growth Factor

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The role of placental growth factor in regulating fetal brain vascular development

Reproduction Abstracts ◽

10.1530/repabs.1.p272 ◽

2014 ◽

Author(s):

Matthew T Ratsep ◽

Bruno Zavan ◽

Nicki Peterson ◽

Leandra Tolusso ◽

Vanessa Kay ◽

...

Keyword(s):

Growth Factor ◽

Vascular Development ◽

Fetal Brain ◽

Placental Growth Factor

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Telmisartan in High Cardiovascular Risk Patients

European Cardiology Review ◽

10.15420/ecr.2012.8.1.10 ◽

2012 ◽

Vol 8 (1) ◽

pp. 10 ◽

Cited By ~ 1

Author(s):

Roland Asmar ◽

Keyword(s):

Cardiovascular Disease ◽

Cardiovascular Risk ◽

Ace Inhibitors ◽

Angiotensin Receptor Blockers ◽

High Cardiovascular Risk ◽

Raas Blockade ◽

Risk Patients ◽

Receptor Blockers ◽

Current Guidelines

The worldwide morbidity and mortality burden of cardiovascular disease (CVD) is overwhelming and caused by increasing life expectancy and an epidemic of risk factors, including hypertension. Therapeutic options targeting different areas of the renin–angiotensin–aldosterone system (RAAS) to disrupt pathophysiological processes along the cardiovascular continuum are available. Angiotensin-converting enzyme (ACE) inhibitors are first-line treatments for CVD and angiotensin receptor blockers (ARBs) are suitable alternatives. Both ACE inhibitors and ARBs prevent CVD by lowering blood pressure (BP). Additionally, several studies have demonstrated that RAAS blockade can reduce cardiovascular risk beyond what might be expected from BP lowering alone. However, the ARBs are not all equally effective. Telmisartan is a long-lasting ARB that effectively controls BP over the full 24-hour period. Recently, the Ongoing telmisartan alone and in combination with ramipril global endpoint trial (ONTARGET) study showed that telmisartan reduces cardiovascular events in high cardiovascular risk patients similarly to the gold standard ACE inhibitor ramipril beyond BP lowering alone, but with a better tolerability. Based on the results of the ONTARGET and Telmisartan randomized assessment study in ACE intolerant subjects with cardiovascular disease (TRANSCEND) studies, telmisartan is indicated for the reduction of cardiovascular morbidity. This article aims to review current guidelines for the management of CVD and consider key data from clinical trials and clinical practice evaluating the role of telmisartan in CVD.

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Hyperglycaemia up-regulates placental growth factor (PlGF) expression and secretion in endothelial cells via suppression of PI3 kinase-Akt signalling and activation of FOXO1

Scientific Reports ◽

10.1038/s41598-021-95511-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Samir Sissaoui ◽

Stuart Egginton ◽

Ling Ting ◽

Asif Ahmed ◽

Peter W. Hewett

Keyword(s):

Endothelial Cells ◽

Growth Factor ◽

Endothelial Dysfunction ◽

Akt Activation ◽

Forkhead Box ◽

Pi3k Activity ◽

Binding Sequence

AbstractPlacenta growth factor (PlGF) is a pro-inflammatory angiogenic mediator that promotes many pathologies including diabetic complications and atherosclerosis. Widespread endothelial dysfunction precedes the onset of these conditions. As very little is known of the mechanism(s) controlling PlGF expression in pathology we investigated the role of hyperglycaemia in the regulation of PlGF production in endothelial cells. Hyperglycaemia stimulated PlGF secretion in cultured primary endothelial cells, which was suppressed by IGF-1-mediated PI3K/Akt activation. Inhibition of PI3K activity resulted in significant PlGF mRNA up-regulation and protein secretion. Similarly, loss or inhibition of Akt activity significantly increased basal PlGF expression and prevented any further PlGF secretion in hyperglycaemia. Conversely, constitutive Akt activation blocked PlGF secretion irrespective of upstream PI3K activity demonstrating that Akt is a central regulator of PlGF expression. Knock-down of the Forkhead box O-1 (FOXO1) transcription factor, which is negatively regulated by Akt, suppressed both basal and hyperglycaemia-induced PlGF secretion, whilst FOXO1 gain-of-function up-regulated PlGF in vitro and in vivo. FOXO1 association to a FOXO binding sequence identified in the PlGF promoter also increased in hyperglycaemia. This study identifies the PI3K/Akt/FOXO1 signalling axis as a key regulator of PlGF expression and unifying pathway by which PlGF may contribute to common disorders characterised by endothelial dysfunction, providing a target for therapy.

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Role of placental growth factor in glucose metabolism

Journal of Thrombosis and Haemostasis ◽

10.1111/j.1538-7836.2006.02104.x ◽

2006 ◽

Vol 4 (9) ◽

pp. 2098-2099 ◽

Cited By ~ 2

Author(s):

G. VOROS ◽

H. R. LIJNEN

Keyword(s):

Growth Factor ◽

Glucose Metabolism ◽

Placental Growth Factor

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Novel signal transduction targets in cardiovascular disease: Role of platelet-derived growth factor in vascular smooth muscle cell proliferation

Drug Development Research ◽

10.1002/ddr.430290210 ◽

1993 ◽

Vol 29 (2) ◽

pp. 148-157 ◽

Cited By ~ 3

Author(s):

Christopher J. Molloy

Keyword(s):

Cardiovascular Disease ◽

Signal Transduction ◽

Cell Proliferation ◽

Smooth Muscle ◽

Growth Factor ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Platelet Derived Growth Factor

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Hormonal and Sex Impact on the Epidemiology of Canine Lymphoma

Journal of Cancer Epidemiology ◽

10.1155/2009/591753 ◽

2009 ◽

Vol 2009 ◽

pp. 1-7 ◽

Cited By ~ 34

Author(s):

J. Armando Villamil ◽

Carolyn J. Henry ◽

Allen W. Hahn ◽

Jeffrey N. Bryan ◽

Jeff W. Tyler ◽

...

Keyword(s):

Lower Risk ◽

Protective Role ◽

Large Animal Model ◽

Large Animal ◽

Medical Database ◽

Canine Lymphoma ◽

Non Hodgkin Lymphoma ◽

Risk Ratios ◽

Lymphoma Risk

The Surveillance Epidemiology and End Results data demonstrate that the risk of non-Hodgkin lymphoma is lower for women, but that the incidence increases after fifty years of age, at which menopause is regularly reached, suggesting that female hormones may be protective for NHL. This study examines the influence of sex on lymphoma risk in a relevant large animal model. Records for dogs in the Veterinary Medical Database were analyzed from 1964 to 2002. Risk ratios were calculated to evaluate associations between sex, neutering status, and lymphoma occurrence. A total of 14,573 cases and 1,157,342 controls were identified. Intact females had a significantly lower risk of developing lymphoma, Odds Ratio 0.69 (0.63–0.74) with aP<.001. We conclude that there is a sex effect on NHL risk in dogs similar to humans. We hypothesize that the hormone levels of intact females lower the risk of NHL. The possibility of a protective role of endogenous estrogens in the etiology of NHL should be investigated.

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