Heparin binding EGF is necessary for vasospastic response to endothelin

Chansel, Dominique; Ciroldi, Magali; Vandermeersch, Sophie; Jackson, Leslie F.; Gómez, Ana-María; Henrion, Didier; Lee, Dong Hoon; Coffman, Thomas M.; Richard, Sylvain; Dussaule, Jean–Claude; Tharaux, Pierre‐Louis

doi:10.1096/fj.05-5328fje

Cited by 61 publications

(48 citation statements)

References 59 publications

(63 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…38 Finally, EGFR also controls PI3K activity both in the endothelium and smooth muscle cells as demonstrated previously using pharmacological agents and the wa-2 mice. 39,40 Further studies should address this point.…”

Section: Discussionmentioning

confidence: 98%

Epidermal Growth Factor Receptor Mediates the Vascular Dysfunction But Not the Remodeling Induced by Aldosterone/Salt

et al. 2011

View full text Add to dashboard Cite

Abstract-Pathophysiological aldosterone (aldo)/mineralocorticoid receptor signaling has a major impact on the cardiovascular system, resulting in hypertension and vascular remodeling. Mineralocorticoids induce endothelial dysfunction, decreasing vasorelaxation in response to acetylcholine and increasing the response to vasoconstrictors. Activation of the epidermal growth factor receptor (EGFR) is thought to mediate the vascular effects of aldo, but this has yet to be demonstrated in vivo. In this study, we analyzed the molecular and functional vascular consequences of aldo-salt challenge in the waved 2 mouse, a genetic model with a partial loss of EGFR tyrosine kinase activity. Deficient EGFR activity is associated with global oxidative stress and endothelial dysfunction. A decrease in EGFR activity did not affect the arterial wall remodeling process induced by aldo-salt. By contrast, normal EGFR activity was required for the aldo-induced enhancement of phenylephrine-and angiotensin II-mediated vasoconstriction. In conclusion, this in vivo study demonstrates that EGFR plays a key role in aldosterone-mediated vascular reactivity. Clinical trials (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study and Randomized Aldactone Evaluation Study) have demonstrated the beneficial effects of administering low doses of pharmacological antagonists of the mineralocorticoid receptor (MR; the receptor of the mineralocorticoid hormone aldosterone [aldo]) to patients with heart failure, with improvements in survival rate and morbidity. 1,2 These clinical benefits may partly result from improved vascular function. 3 The MR is expressed in both endothelium and smooth muscle, 4 and the vessels are now considered to be direct targets of aldo. 5 In the mouse, the 11␤-hydroxysteroid dehydrogenase type II enzyme is expressed in the endothelium but not in the smooth muscle, 4,6 at variance with humans. 7 Therefore, in the mouse, aldo is the specific ligand of the MR in the endothelium but not in the smooth muscle, where glucocorticoids could also activate MR. MR activation affects endothelial function and vascular tone: aldo infusion induces endothelial dysfunction, decreasing vasorelaxation in response to acetylcholine (Ach), and increasing the response to various vasoconstrictors. 5,8,9 We showed recently that an increase in MR signaling in the endothelium is associated with an increase in blood pressure and altered vascular tone. 4 Moreover, patients with primary aldosteronism have a higher aortic wall thickness than those with primary hypertension. 10 Aldo is, thus, recognized as a cardiovascular risk factor that exacerbates vascular injury, 3 although the underlying mechanisms remain unclear.It has been suggested that the epidermal growth factor receptor (EGFR) could play a key role in the cardiovascular effects of aldo. 11 In cultured cells, downstream EGFR signaling cascades are induced by aldo or prevented by MR blockade on aldo stimulation. 12 Increases in EGFR expression and/or activation have...

show abstract

Section: Discussionmentioning

confidence: 98%

Epidermal Growth Factor Receptor Mediates the Vascular Dysfunction But Not the Remodeling Induced by Aldosterone/Salt

et al. 2011

View full text Add to dashboard Cite

show abstract

“…28 In CKD, increases in parathyroid or renal expression of EGFR ligands and/or G protein-coupled receptor (GPCR) ligands, known to transactivate the EGFR, could further aggravate the severity of EGFR-driven growth and VDR reduction induced by TGF-␣. 14,29 Indeed, EGFR transactivation upon binding to their cognate G protein-coupled receptor mediates the mitogenic properties of molecules that circulate at high levels in patients with CKD, including endothelin I, 30 -32 prostaglandin E2, 33 and AngII, 34,35 in the vasculature and in the hypertrophic growth of cardiac myocytes 30,33,34,36 ; therefore, in CKD, progressive decreases in VDR levels induced by increased EGFR activation/transactivation, at multiple sites in addition to the PTG, could partially account for the resistance to calcitriol antiproliferative and anti-inflammatory actions that accelerate the progression of SH and renal and cardiovascular disorders. BASIC RESEARCH www.jasn.org TGF-␣/EGFR induction of LIP synthesis contributes to the link between severe EGFR-driven growth and VDR reduction.…”

Section: Discussionmentioning

confidence: 99%

EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

Arcidiacono

Sato²,

Alvarez-Hernandez³

et al. 2008

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Calcitriol, acting through vitamin D receptors (VDR) in the parathyroid, suppresses parathyroid hormone synthesis and cell proliferation. In secondary hyperparathyroidism (SH), VDR content is reduced as hyperplasia becomes more severe, limiting the efficacy of calcitriol. In a rat model of SH, activation of the EGF receptor (EGFR) by TGF-␣ is required for the development of parathyroid hyperplasia, but the relationship between EGFR activation and reduced VDR content is unknown. With the use of the same rat model, it was found that pharmacologic inhibition of EGFR activation with erlotinib prevented the upregulation of parathyroid TGF-␣, the progression of growth, and the reduction of VDR. Increased TGF-␣/EGFR activation induced the synthesis of liver-enriched inhibitory protein, a potent mitogen and the dominant negative isoform of the transcription factor CCAAT enhancer binding protein-␤, in human hyperplastic parathyroid glands and in the human epidermoid carcinoma cell line A431, which mimics hyperplastic parathyroid cells. Increases in liver-enriched inhibitory protein directly correlated with proliferating activity and, in A431 cells, reduced VDR expression by antagonizing CCAAT enhancer binding protein-␤ transactivation of the VDR gene. Similarly, in nodular hyperplasia, which is the most severe form of SH and the most resistant to calcitriol therapy, higher TGF-␣ activation of the EGFR was associated with an 80% reduction in VDR mRNA levels. Thus, in SH, EGFR activation is the cause of both hyperplastic growth and VDR reduction and therefore influences the efficacy of therapy with calcitriol.

show abstract

“…6,9 Pathophysiological effects of EGFR include cell transformation and tumorigenesis, as well as parainflammatory dysregulation of tissue homeostasis, leading, for example, to vascular dysfunction and fibrosis. 6 There are several reports suggesting that EGFR transactivation is responsible for Gprotein-coupled receptor-mediated ERK1/2 phosphorylation (eg, induced by angiotensin II [ang II], 10,11 ␣ 1 -and ␤-adrenergic agonists, 12,13 thrombin, 14 endothelin-1 [ET-1], [15][16][17] and purinergic receptor ligands 18 ) and the resulting pathophysiological effects on VSMC and vascular function, including atherosclerosis. 6 However, other hormones also, such as steroids 19 or prostaglandins 20 as well as reactive oxygen species 21 and cardiotonic steroids, 22 (mis)use the EGFR as signal transducer.…”

mentioning

confidence: 99%

“…For ang II and ET-1, a small contribution of EGFR to Ca 2ϩ signaling in VSMC has been suggested on the basis of pharmacological data. 17,33 Thus, EGFR is not only relevant for mitogen-activated protein kinase but also for Ca 2ϩ signaling. Most of the studies that have been performed relied on pharmacological or immunologic tools to unveil the contribution of EGFR to the aforementioned deleterious effects on vascular tissue homeostasis.…”

mentioning

confidence: 99%

Consequences of Epidermal Growth Factor Receptor (ErbB1) Loss for Vascular Smooth Muscle Cells From Mice With Targeted Deletion of ErbB1

Schreier

Döhler²,

Rabe³

et al. 2011

ATVB

View full text Add to dashboard Cite

Objective— Pathophysiological effects of the epidermal growth factor receptor (EGFR or ErbB1) include vascular remodeling. EGFR transactivation is proposed to contribute significantly to heterologous signaling and remodeling in vascular smooth muscle cells (VSMC). Methods and Results— We investigated the importance of EGFR in primary VSMC from aorta of mice with targeted deletion of the EGFR ( EGFR Δ/Δ VSMC →VSMC EGFR−/− and EGFR Δ/+ VSMC →VSMC EGFR+/− ) and the respective littermate controls ( EGFR +/+ VSMC →VSMC EGFR+/+ ) with respect to survival, pentose phosphate pathway activity, matrix homeostasis, extracellular signal–regulated kinase 1/2 (ERK1/2) phosphorylation, and Ca 2+ homeostasis. In VSMC EGFR−/− , epidermal growth factor–induced signaling was abolished; VSMC EGFR+/− showed an intermediate phenotype. EGFR deletion enhanced spontaneous cell death, reduced pentose phosphate pathway activity, disturbed cellular matrix homeostasis (collagen III and fibronectin), and abolished epidermal growth factor sensitivity. In VSMC EGFR−/− endothelin-1- or α 1 -adrenoceptor-induced ERK1/2 phosphorylation and the fraction of Ca 2+ responders were significantly reduced, whereas responsive cells showed a significantly stronger Ca 2+ signal. Oxidative stress (H 2 O 2 ) induced ERK1/2 activation in VSMC EGFR+/+ and VSMC EGFR+/− but not in VSMC EGFR−/− . The Ca 2+ signal was enhanced in VSMC EGFR−/− , similar to purinergic stimulation by ATP. Conclusion— In conclusion, EGFR was found to be important for basal VSMC homeostasis and ERK1/2 activation by the tested G-protein–coupled receptors or radical stress. Ca 2+ signaling was modulated by EGFR differentially with respect to the fraction of responders and magnitude of the signal. Thus, EGFR seems to be Janus-faced for VSMC biology.

show abstract

Heparin binding EGF is necessary for vasospastic response to endothelin

Cited by 61 publications

References 59 publications

Epidermal Growth Factor Receptor Mediates the Vascular Dysfunction But Not the Remodeling Induced by Aldosterone/Salt

Epidermal Growth Factor Receptor Mediates the Vascular Dysfunction But Not the Remodeling Induced by Aldosterone/Salt

EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

Consequences of Epidermal Growth Factor Receptor (ErbB1) Loss for Vascular Smooth Muscle Cells From Mice With Targeted Deletion of ErbB1

Contact Info

Product

Resources

About