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

Schreier, Barbara; Döhler, Maria; Rabe, Sindy; Schneider, B.; Schwerdt, Gerald; Ruhs, Stefanie; Sibilia, Maria; Gotthardt, Michael; Gekle, Michael; Großmann, Claudia

doi:10.1161/atvbaha.111.223537

Cited by 35 publications

(45 citation statements)

References 62 publications

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“…[22][23][24][25][26] As demonstrated earlier, 22 EGFR expression was almost abolished in the aortas ( Figure 1A), indicating a deletion of EGFR in VSMC. This result was confirmed by primary culture of VSMC demonstrating a reduction to 10±5% compared with controls.…”

Section: Expression Of Erbb Receptors In Aortas and Hearts Of Egfr δ/supporting

confidence: 75%

“…This result was confirmed by primary culture of VSMC demonstrating a reduction to 10±5% compared with controls. 22 In lung, liver, and kidney, EGFR expression was unchanged (Table S2). In the heart, where the SM22 promoter is active during embryogenesis, 25,26 expression of EGFR was reduced by one third ( Figure 1A).…”

Section: Expression Of Erbb Receptors In Aortas and Hearts Of Egfr δ/mentioning

confidence: 99%

“…To ensure that reduced cardiac EGFR expression resulted from cardiomyocytes, we analyzed isolated cardiomyocytes and observed a significant decrease in EGFR expression on mRNA level ( Figure 1A) and protein level (41±13% of con; n=11; Figure 1C). 22 Because EGF can also exert its intracellular effects by binding to a heterodimer consisting of the receptors ErbB2 and ErbB3, we analyzed mRNA expression for these receptors in hearts, aortas, and isolated cardiomyocytes. Only the expression of ErbB3 mRNA was reduced in aortas of KO animals (Table S2).…”

Section: Expression Of Erbb Receptors In Aortas and Hearts Of Egfr δ/mentioning

confidence: 99%

“…There was no difference in systolic blood pressure (SBP) and heart rate in conscious animals determined by the tail cuff method as indicated by preliminary measurements. 22 As tail cuff does not allow reliable assessment of diastolic blood pressure (DBP), we performed measurements in anesthetized animals using a Millar catheter. During ketamine/xylazine anesthesia, we detected a reduced DBP in KO animals, as well as mean arterial blood pressure.…”

Section: Blood Pressure and Heart Ratementioning

confidence: 99%

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Loss of Epidermal Growth Factor Receptor in Vascular Smooth Muscle Cells and Cardiomyocytes Causes Arterial Hypotension and Cardiac Hypertrophy

et al. 2013

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Abstract-The epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, contributes to parainflammatory dysregulation, possibly causing cardiovascular dysfunction and remodeling. The physiological role of cardiovascular EGFR is not completely understood. To investigate the physiological importance of EGFR in vascular smooth muscle cells and cardiomyocytes, we generated a mouse model with targeted deletion of the EGFR using the SM22 (smooth muscle-specific protein 22) promoter. While the reproduction of knockout animals was not impaired, life span was significantly reduced. Systolic blood pressure was not different between the 2 genotypes-neither in tail cuff nor in intravascular measurementswhereas total peripheral vascular resistance, diastolic blood pressure, and mean blood pressure were reduced. Loss of vascular smooth muscle cell-EGFR results in a dilated vascular phenotype with minor signs of fibrosis and inflammation. Echocardiography, necropsy, and histology revealed a dramatic eccentric cardiac hypertrophy in knockout mice (2.5-fold increase in heart weight), with increased stroke volume and cardiac output as well as left ventricular wall thickness and lumen. Cardiac hypertrophy is accompanied by an increase in cardiomyocyte volume, a strong tendency to cardiac fibrosis and inflammation, as well as enhanced NADPH-oxidase 4 and hypertrophy marker expression. Thus, in cardiomyocytes, EGFR prevents excessive hypertrophic growth through its impact on reactive oxygen species balance, whereas in vascular smooth muscle cells EGFR contributes to the appropriate vascular wall architecture and vessel reactivity, thereby supporting a physiological vascular tone.

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Section: Expression Of Erbb Receptors In Aortas and Hearts Of Egfr δ/supporting

confidence: 75%

Section: Expression Of Erbb Receptors In Aortas and Hearts Of Egfr δ/mentioning

confidence: 99%

Section: Expression Of Erbb Receptors In Aortas and Hearts Of Egfr δ/mentioning

confidence: 99%

Section: Blood Pressure and Heart Ratementioning

confidence: 99%

See 2 more Smart Citations

Loss of Epidermal Growth Factor Receptor in Vascular Smooth Muscle Cells and Cardiomyocytes Causes Arterial Hypotension and Cardiac Hypertrophy

et al. 2013

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“…In a variety of cells, we and others have previously demonstrated that AT 1 R activation leads to phosphorylation of the ErbB1 receptor, downstream signalling and subsequent changes in cell physiology (Thomas et al, 2002;Ohtsu et al, 2006b). Moreover, deletion of ErbB1 in vascular smooth muscle cells reduces GPCR-mediated signalling and has marked effects on vascular and cardiac remodelling (Schreier et al, 2011;Schreier et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Investigations into the role of the ErbB4 receptor in cardiomyocyte hypertrophy and adult cardiac function

Wang¹

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ErbB receptors (ErbB1 -ErbB4) are a subfamily of tyrosine kinase receptors that regulate cell proliferation and differentiation. It has been proposed that the ErbB1 subtype is transactivated by Ang II to mediate cardiac hypertrophy. However, whether other ErbB receptors, in particular the abundant subtype ErbB4, are involved in this process is not known. ErbB4 has four isoforms due to alternative splicing, each of which might play a distinct role in regulating cell activity. However, the role of individual ErbB4 isoforms in hypertrophic signalling has not been investigated. In addition, ErbB4 activation is critical for cardiac development, cardiomyocyte survival in various rodent models of cardiovascular pathologies. However, the physiological role of ErbB4 in the adult heart remains poorly understood. The overall aim of my PhD project is to examine the role of the ErbB4 receptor in mediating hypertrophic growth of cardiomyocytes in vitro, and maintenance of the adult heart in vivo.To investigate the role of ErbB1, ErbB2 and ErbB4 in mediating hypertrophy, I inhibited individual ErbB receptors in primary neonatal rat ventricular cardiomyocytes using RNA interference or a pharmacological inhibitor (AG1478). Hypertrophy induced with Ang II (100 nM) or NRG1 (10 nM) was assessed by measuring the promoter activity of hypertrophic genes, ERK1/2 activation, and hypertrophic growth. The NRG1-induced hypertrophy was reduced by down-regulation of Following the studies above, I investigated whether the different ErbB4 isoforms had any functional differences in the cardiomyocytes. Irrespective of any changes in total ErbB4 mRNA levels, expression of the non-cleavable JM-b isoform was always predominant in adult heart in both physiological and pathological conditions. Although the cleavable isoform JM-a was detectable, it is not cleaved in cardiomyocytes. I replaced the endogenous ErbB4 with exogenous individual isoform in cardiomyocytes and found that all four isoforms of ErbB4 could mediate the NRG1-induced hypertrophic signalling. This suggests that the hypertrophy is triggered by a common feature of the four isoforms (ostensibly the kinase activity), and appears independent of isoformspecific features, such as the cleavable domain.To investigate the physiological function of ErbB4 in adult heart, we adopted the tamoxifeniii inducible αMHC-MerCreMer/loxP system to induce ErbB4 deletion from cardiomyocytes in the adult mouse. The expression of ErbB4 was reduced by ~ 90% at 10 days after tamoxifen treatment. Echocardiography revealed no differences in cardiac function (fractional shortening) betweenErbB4-conditional knockout (ErbB4-cKO) and control groups at 3-4 months after deletion of ErbB4. However, the heart weight was increased in ErbB4-cKO animals. Interestingly, there is no change in cardiac structure (cardiomyocyte size and cardiac fibrosis) or the expression of genes associated with pathological hypertrophy. This suggests that the cardiac hypertrophy observed following ErbB4 deletion may be physiological, a...

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Conserved signaling mechanisms in Drosophila heart development

Ahmad

2017

Developmental Dynamics

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Signal transduction through multiple distinct pathways regulates and orchestrates the numerous biological processes comprising heart development. This review outlines the roles of the FGFR, EGFR, Wnt, BMP, Notch, Hedgehog, Slit/ Robo, and other signaling pathways during four sequential phases of Drosophila cardiogenesis-mesoderm migration, cardiac mesoderm establishment, differentiation of the cardiac mesoderm into distinct cardiac cell types, and morphogenesis of the heart and its lumen based on the proper positioning and cell shape changes of these differentiated cardiac cells-and illustrates how these same cardiogenic roles are conserved in vertebrates. Mechanisms bringing about the regulation and combinatorial integration of these diverse signaling pathways in Drosophila are also described. This synopsis of our present state of knowledge of conserved signaling pathways in Drosophila cardiogenesis and the means by which it was acquired should facilitate our understanding of and investigations into related processes in vertebrates. Developmental Dynamics 246:641-656, 2017. V C 2017 Wiley Periodicals, Inc.

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

Cited by 35 publications

References 62 publications

Loss of Epidermal Growth Factor Receptor in Vascular Smooth Muscle Cells and Cardiomyocytes Causes Arterial Hypotension and Cardiac Hypertrophy

Loss of Epidermal Growth Factor Receptor in Vascular Smooth Muscle Cells and Cardiomyocytes Causes Arterial Hypotension and Cardiac Hypertrophy

Investigations into the role of the ErbB4 receptor in cardiomyocyte hypertrophy and adult cardiac function

Conserved signaling mechanisms in Drosophila heart development

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