Adenoviral transduction of EGFR into pregnancy-adapted uterine artery endothelial cells remaps growth factor induction of endothelial dysfunction

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.

Download Full-text

Effects of Hypocrellin A on Expression of Vascular Endothelial Growth Factor and Endothelin-1 in Human Umbilical Endothelial Cells

The American Journal of Chinese Medicine ◽

10.1142/s0192415x0700520x ◽

2007 ◽

Vol 35 (04) ◽

pp. 713-723 ◽

Cited By ~ 2

Author(s):

Lei Dang ◽

J. Paul Seale ◽

Xianqin Qu

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Endothelial Dysfunction ◽

Protein Expression ◽

Vascular Endothelial ◽

Naturally Occurring ◽

Hypocrellin A ◽

Endothelial Growth Factor ◽

Vegf Protein

Increased endothelin-1 (ET-1), vascular endothelial growth factor (VEGF) and activation of protein kinase C (PKC) are co-contributors to endothelial hyperpermeability in diabetes. Several lines of evidence have suggested a hypothesis that activation of specific PKC isoforms are the causative factor in ET-1 and VEGF mediated endothelial dysfunction. In the present study, we tested this hypothesis with hypocrellin A, a naturally occurring PKC inhibitor from a Chinese plant. Human umbilical vein endothelial cells (HUVECs) were incubated with 20 mM glucose in both the presence and absence of hypocrellin A, after which, the protein expression and release of VEGF and mRNA expression and release of ET-1 were measured. VEGF and ET-1 were released into the medium and expressions of VEGF protein and ET-1 mRNA were significantly increased in HUVECs incubated with 20 mM glucose. Hypocrellin A (150 nM) significantly decreased VEGF release (117 ± 3 vs. 180 ± 11 pg/mg, p < 0.05) and VEGF protein expression (from 130 ± 14% to 88 ± 18.5%, p < 0.05). ET-1 release was also reduced in hypocrellin A treated HUVECs (63.3 ± 9.9 vs. 75.2 ± 12.6 ng/mg). Hypocrellin A significantly reversed the effect of high glucose on ET-1 mRNA expression ( p < 0.05). The results revealed that PKC activation plays a pivotal role in VEGF and ET-1 mediated endothelial permeability. The naturally occurring compound hypocrellin A may be a potentially novel treatment for endothelial dysfunction in diabetes.

Download Full-text

FGF23 impairs peripheral microvascular function in renal failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00272.2018 ◽

2018 ◽

Vol 315 (5) ◽

pp. H1414-H1424 ◽

Cited By ~ 8

Author(s):

Melissa Verkaik ◽

Rio P. Juni ◽

Ellen P. M. van Loon ◽

Erik M. van Poelgeest ◽

Rick F. J. Kwekkeboom ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Endothelial Cells ◽

Growth Factor ◽

Endothelial Dysfunction ◽

Kidney Disease ◽

Asymmetric Dimethylarginine ◽

Ex Vivo ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth

Cardiovascular diseases account for ~50% of mortality in patients with chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF23) is independently associated with endothelial dysfunction and cardiovascular mortality. We hypothesized that CKD impairs microvascular endothelial function and that this can be attributed to FGF23. Mice were subjected to partial nephrectomy (5/6Nx) or sham surgery. To evaluate the functional role of FGF23, non-CKD mice received FGF23 injections and CKD mice received FGF23-blocking antibodies after 5/6Nx surgery. To examine microvascular function, myocardial perfusion in vivo and vascular function of gracilis resistance arteries ex vivo were assessed in mice. 5/6Nx surgery blunted ex vivo vasodilator responses to acetylcholine, whereas responses to sodium nitroprusside or endothelin were normal. In vivo FGF23 injections in non-CKD mice mimicked this endothelial defect, and FGF23 antibodies in 5/6Nx mice prevented endothelial dysfunction. Stimulation of microvascular endothelial cells with FGF23 in vitro did not induce ERK phosphorylation. Increased plasma asymmetric dimethylarginine concentrations were increased by FGF23 and strongly correlated with endothelial dysfunction. Increased FGF23 concentration did not mimic impaired endothelial function in the myocardium of 5/6Nx mice. In conclusion, impaired peripheral endothelium-dependent vasodilatation in 5/6Nx mice is mediated by FGF23 and can be prevented by blocking FGF23. These data corroborate FGF23 as an important target to combat cardiovascular disease in CKD.NEW & NOTEWORTHY In the present study, we provide the first evidence that fibroblast growth factor 23 (FGF23) is a cause of peripheral endothelial dysfunction in a model of early chronic kidney disease (CKD) and that endothelial dysfunction in CKD can be prevented by blockade of FGF23. This pathological effect on endothelial cells was induced by long-term exposure of physiological levels of FGF23. Mechanistically, increased plasma asymmetric dimethylarginine concentrations were strongly associated with this endothelial dysfunction in CKD and were increased by FGF23.

Download Full-text

Pre-Clinical Investigation of Cardioprotective Beta-Blockers as a Therapeutic Strategy for Preeclampsia

Journal of Clinical Medicine ◽

10.3390/jcm10153384 ◽

2021 ◽

Vol 10 (15) ◽

pp. 3384

Author(s):

Natalie K. Binder ◽

Teresa M. MacDonald ◽

Sally A. Beard ◽

Natasha de Alwis ◽

Stephen Tong ◽

...

Keyword(s):

Heart Failure ◽

Cardiovascular Disease ◽

Endothelial Cells ◽

Growth Factor ◽

Endothelial Dysfunction ◽

Beta Blockers ◽

Angiogenic Factors ◽

Heme Oxygenase 1 ◽

Positive Effects ◽

Markers Of Inflammation

Despite significant maternal and fetal morbidity, a treatment for preeclampsia currently remains an unmet need in clinical care. As too does the lifelong cardiovascular risks imparted on preeclampsia sufferers. Endothelial dysfunction and end-organ injury are synonymous with both preeclampsia and cardiovascular disease, including heart failure. We propose that beta-blockers, known to improve endothelial dysfunction in the treatment of cardiovascular disease, and specifically known to reduce mortality in the treatment of heart failure, may be beneficial in the treatment of preeclampsia. Here, we assessed whether the beta-blockers carvedilol, bisoprolol, and metoprolol could quench the release of anti-angiogenic factors, promote production of pro-angiogenic factors, reduce markers of inflammation, and reduce endothelial dysfunction using our in vitro pre-clinical preeclampsia models encompassing primary placental tissue and endothelial cells. Here, we show beta-blockers effected a modest reduction in secretion of anti-angiogenic soluble fms-like tyrosine kinase-1 and soluble endoglin and increased expression of pro-angiogenic placental growth factor, vascular endothelial growth factor and adrenomedullin in endothelial cells. Beta-blocker treatment mitigated inflammatory changes occurring after endothelial dysfunction and promoted cytoprotective antioxidant heme oxygenase-1. The positive effects of the beta-blockers were predominantly seen in endothelial cells, with a less consistent response seen in placental cells/tissue. In conclusion, beta-blockers show potential as a novel therapeutic approach in the treatment of preeclampsia and warrant further investigation.

Download Full-text

Diagnostic and prognostic value of endothelial dysfunction markers in patients with ulcerative colitis

Kazan medical journal ◽

10.17750/kmj2016-187 ◽

2016 ◽

Vol 97 (2) ◽

pp. 187-191 ◽

Cited By ~ 1

Author(s):

E A Stepina ◽

O V Khlynova ◽

A V Tuev

Keyword(s):

Ulcerative Colitis ◽

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Endothelial Dysfunction ◽

Pathological Process ◽

Control Group ◽

Vascular Endothelial ◽

Disease Attack ◽

Endothelial Growth Factor

Aim. To assess the endothelial dysfunction degree in patients with ulcerative colitis, depending on the disease attack severity, the pathological process spread, the presence of systemic manifestations, complications, and endoscopic activity of the process.Methods. 45 patients with an established diagnosis of «ulcerative colitis» in the exacerbation phase and with newly diagnosed disease forms were examined. The control group included 11 apparently healthy people. As endothelial dysfunction markers vascular endothelial growth factor levels in serum and blood plasma desquamated endothelial cells amount were studied.Results.In the group of patients with ulcerative colitis a statistically significant increase in levels of endothelial dysfunction markers (the vascular endothelial growth factor content was 506.40±287.00 pg/ml, the plasma desquamated endothelial cells number - 6.47±4.22×104/L) was found compared with the control group (pConclusion. In patients with ulcerative colitis endothelial dysfunction, correlated with disease activity and severity markers, was revealed; vascular endothelial growth factor levels and plasma desquamated endothelial cells number can serve as the ulcerative colitis severity criteria, as well as a sign of unfavorable disease course.

Download Full-text