Int. J. Mol. Sci. 2013, 14(10), 20597-20613; doi:10.3390/ijms141020597

The Epidermal Growth Factor Receptor and Its Ligands in Cardiovascular Disease
Nader Makki 1, Kristina W. Thiel 1 and Francis J. Miller Jr. 1,2,*
Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA; E-Mails: (N.M.); (K.W.T.)
Veterans Affairs Medical Center, Iowa City, IA 52242, USA
Author to whom correspondence should be addressed; E-Mail:; Tel.: +1-319-384-4524; Fax: +1-319-353-5552.
Received: 24 July 2013; in revised form: 20 September 2013 / Accepted: 8 October 2013 /
Published: 15 October 2013


: The epidermal growth factor receptor (EGFR) family and its ligands serve as a switchboard for the regulation of multiple cellular processes. While it is clear that EGFR activity is essential for normal cardiac development, its function in the vasculature and its role in cardiovascular disease are only beginning to be elucidated. In the blood vessel, endothelial cells and smooth muscle cells are both a source and a target of EGF-like ligands. Activation of EGFR has been implicated in blood pressure regulation, endothelial dysfunction, neointimal hyperplasia, atherogenesis, and cardiac remodeling. Furthermore, increased circulating EGF-like ligands may mediate accelerated vascular disease associated with chronic inflammation. Although EGFR inhibitors are currently being used clinically for the treatment of cancer, additional studies are necessary to determine whether abrogation of EGFR signaling is a potential strategy for the treatment of cardiovascular disease.
EGFR; EGF-like ligands; vascular disease; atherosclerosis; cardiac remodeling

1. Introduction

Since the first discovery of the epidermal growth factor receptor (EGFR) in the mid-1970s, over 40,000 papers have described roles in nearly every known cellular process and in numerous disease states. In this review, we focus on the reported activity of EGFR and its ligands in cardiovascular disease.

EGFR is the inaugural member of the ErbB family of receptor tyrosine kinases and consists of an extracellular ligand binding domain, a single α-helical trans-membrane domain, an intracellular tyrosine kinase domain, and a carboxy (C)-terminal region that contains autophosphorylation sites. Upon ligand binding, EGFR undergoes a transition from an inactive monomer to an active homodimer or heterodimer with other ErbB family members (ErbB2/HER2/neu, ErbB3, and ErbB4). EGFR dimerization stimulates its intracellular protein tyrosine kinase activity, leading to autophosphorylation of several tyrosine residues in the C-terminal domain of the EGFR; consequently, it elicits downstream activation and signaling by several other proteins, including mitogen-activated protein kinases (MAPK), phosphoinositide-3 kinase (PI3K), phospholipase C-γ (PLC-γ), and c-Src [1]. As such, EGFR serves as signaling hub, engaging in cross-talk with multiple pathways (Figure 1). The downstream signaling proteins initiate several signal transduction cascades, principally the extracellular signal-regulated kinase (ERK)/MAPK, PI3K/Akt and jun kinase (JNK) pathways, thereby regulating cell proliferation, survival, differentiation, migration, inflammation, and matrix homeostasis [1]. In addition to the classical pathway of activation, EGFR can be activated through G protein-coupled receptors (GPCR) without direct interaction with GPCR agonists, an event referred to as transactivation [2,3]. EGFR transactivation mediates several downstream signaling cascades such as ERK activation [4,5]. These events are mediated by pathways involving classic second messengers (Ca2+, diacylglycerol (DAG)) as well as protein kinases, non-receptors tyrosine kinases, matrix metalloproteinases (MMP), and reactive oxygen species (ROS) [4,6].

In addition to canonical cell-surface EGFR activity, EGFR also localizes to the nucleus via retrograde translocation, where it regulates cell growth via transcriptional activation of cyclin D1 [7,8]. More recently, it has been shown that EGFR is also proteolytically processed, and the intracellular domain fragment is present in both the cytosol and the nucleus [9,10]. Thus, multiple mechanisms exist whereby activated EGFR controls cellular processes.

Ligands of EGFR, which include epidermal growth factor (EGF), transforming growth factor-α (TGF-α), heparin-binding EGF (HB-EGF), amphiregulin (AREG), betacellulin (BTC), and epiregulin (EREG), are synthesized as transmembrane precursors that must be cleaved by MMPs, including the ADAM (a disintegrin and metalloproteinase) family of proteases, to release mature ligands. EGFR ligands are derived from glycoprotein precursors consisting of an extracellular region, a transmembrane domain and a cytoplasmic domain; therefore, proteolytic cleavage can result in release of soluble growth factors [11]. Cleavage occurs between the first and second motifs of the immature ligand precursor, leading to release of the subunit adjacent to the plasma membrane as a mature ligand [12].

While in general the mechanism of cleavage is consistent among the EGFR ligands, some differences have been described. For example, ADAM-mediated liberation of EGF occurs via binding of the ADAM disintegrin domain to EGF and cleavage by its metalloproteinase domain, leading to shedding of mature active EGF [13]. TGF-α is cleaved at two sites within its extracellular domain. The well characterized ADAM17 (also known as tumor necrosis factor-α converting enzyme/TACE) and ADAM10 are capable of cleaving TGF-α at its N-terminal site, but the identity of the C-terminal protease remains unclear [14]. HB-EGF is primarily cleaved by MMP-3 and MMP-7 [15,16]. Thus, activation of EGFR is complex and multifactorial.

2. EGFR in Cardiac Development

EGFR is implicated in proliferation and development of epithelial cells in multiple organs based on evidence that EGFR-deficient mice suffer from abnormalities in the skin, kidney, brain and gastrointestinal tract [1721]. In these surviving mice and in the wa-2 mice (mice with a global reduced EGFR kinase activity) the major cardiac defect is valvular, specifically related to the aortic valve. For example, many wa-2 mice die before weaning. Those surviving to three months develop significantly thicker aortic cusps, culminating in severe aortic stenosis, left ventricular hypertrophy and heart failure [22,23]. Histological examination of hearts from wa-2 mice revealed extensive calcification and inflammatory changes mimicking those of human aortic stenosis [23]. The cell types mostly affected are epithelial and glial. Roles for the other ErbB family members in cardiac development have also been provided by studies of mice deficient in ErbB2 and ErbB4 [24,25]. Furthermore, a single nucleotide polymorphism of ErbB4 is associated with congenital cardiovascular abnormalities in humans, specifically left ventricular outflow tract defects [26]. In addition, mice deficient in EGF-like ligands, such as HB-EGF, have decreased survival and abnormalities in aortic valve and ventricular development similar to those in wa-2 mice and ErbB2-deficient mice [27]. Finally, deficiency of ADAM10 yields similar impairment of heart development, presumably through alterations in EGF-like ligand bioavailability [28]. Taken together, these studies demonstrate essential roles for EGFR family members in normal cardiac development.

3. EGFR and Ligands in the Blood Vessel

Multiple cell types within the vascular wall have the potential to express EGFR family members and EGF-like ligands. All four members of the EGFR family of receptors as well as most EGF-like ligands (HB-EGF, TNF-α, BTC, EREG, and AREG) are expressed by vascular smooth muscle cells (VSMCs), and EGFR has also been reported to be expressed on endothelial cells (ECs) [2931]. In addition, EGFR, HB-EGF, AREG, and EREG are expressed by monocytes and macrophages [30]. Given the contribution of inflammatory cells in vascular diseases such as atherosclerosis, it is important to recognize that these cells provide an additional source for EGF-like ligands. For example, HB-EGF is released by monocytes and acts as a VSMC chemoattractant and mitogen [30].

3.1. Vascular Smooth Muscle Cells (VSMCs)

Early evidence for EGFR function in VSMCs was provided by studies in which treatment with EGF was shown to promote bovine VSMC proliferation [32]. More recently, using mice with targeted deletion of EGFR, Schreier and colleagues investigated the importance of EGFR in VSMCs with respect to survival, cellular proliferation and matrix homeostasis [33]. EGFR deletion in these mice was found to promote cellular death, reduce endothelin-1 (ET-1)- or α1-adrenoreceptor-induced ERK1/2 phosphorylation, and disrupt the response to oxidative stress [33]. Indeed, EGFR is well-known to play a key role in the mechanisms underlying VSMC proliferation and migration [34,35]. For example, AREG markedly increases growth of VSMCs [29]. In addition, EGF has been shown to increase cytosolic Ca2+ levels and contraction of VSMCs [36].

Transactivation of EGFR by angiotensin II (AngII), ET-1, or bradykinin involves ROS-dependent activation of c-Src, which then activates EGFR and leads to ERK activation and pro-growth signaling [3739]. ET-1, through acting on ET-1 receptors, has been shown to induce vascular contraction as well as DNA synthesis by transactivating EGFR, which in turn activates the ERK/MAPK pathway [40,41]. VSMC proliferation in response to thrombin also involves EGFR transactivation [42,43].

In addition, Ang II activates EGFR by inducing shedding of pro-HB-EGF by ADAM17; this also leads to activation of ERK as well as PI3K/Akt pathways and VSMC hypertrophy, migration, and proliferation [30,44,45]. This pathway requires second messengers such as Ca2+ and ROS and involves phosphorylation by ADAM kinases [30,46]. Similar mechanisms of EGFR transactivation have been proposed for other GPCRs [39,43]. Of note, MMPs and ADAMs contain cysteine residues that are redox sensitive [47]. Recently it has been shown that caveolin-1, the major structural protein of caveolae, negatively regulates expression of ADAM17 in cultured VSMCs, suggesting a potential role for lipid rafts in regulating EGFR activation [48].

Studies from our group have provided a link between EGFR and the NADPH oxidase Nox1, with consequences for proliferation and migration of VSMCs. First, EGFR is transactivated upon thrombin activation of Nox1 [49]. This mechanism involves ROS-dependent MMP shedding of EGF-like ligands, which in turn activate EGFR and downstream PI3K/Akt. Second, migration of VSMCs in response to thrombin also occurs via Nox1 transactivation of EGFR. The EGFR downstream effector ERK induces MMP-9 activity and N-cadherin shedding, thereby promoting VSMC migration [43]. In addition to acting as an upstream regulator of EGFR activation, Nox1 is also downstream of EGFR. For example, extracellular oxidative stress activates EGFR through metalloproteinase-mediated shedding of EGF-like ligands, leading to ERK-dependent activation of the transcription factor ATF-1 and subsequent expression of Nox1 and cell proliferation [50]. We also recently reported that treatment of cultured monkey VSMCs with EGF-like ligands increases expression of Nox1 as well as Nox1-dependent ROS production [31].

3.2. Endothelial Cells

As compared to VSMCs, the effect of EGFR activation in ECs has not been as well characterized. Both EGFR transactivation by GPCRs and classical activation by EGF-like ligands participate in EC function. For example, ET-1 activation of cyclooxygenase 2 in microvascular ECs involves transactivation of EGFR [51]. Treatment with HB-EGF induces endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) production in human umbilical vein endothelial cells (HUVECs) [52]. Furthermore, HB-EGF induces dilation of arterioles, which can be prevented by inhibition of NOS or by an endothelin B receptor antagonist [53].

4. EGFR and Its Ligands in Cardiovascular Disease

EGFR activated signaling pathways control cell proliferation, apoptosis, angiogenesis and metastatic spread in several different human cancers. Despite a clear role for EGFR activation in the development of cancer, a disease with many similarities to SMC activation following vascular injury, the role of EGFR in vascular disease is poorly defined. In this section, we describe the current knowledge in the field (Figure 2).

4.1. Blood Pressure Regulation

The result of EGFR activation on blood pressure depends on the sum of the effects on endothelial vasodilator release and smooth muscle contraction. As described above, EGF can increase the expression and activation of endothelial NOS and cause vascular dilation [52,53]. In addition, EGF causes VSMC contraction [36] and mediates ET-1 vasoconstriction [41]. Recently, it was shown that mice with smooth muscle targeted deletion of EGFR have reduced diastolic and mean blood pressures, whereas systolic blood pressures are no different [54]. Furthermore, myogenic tone of coronary arterioles is mediated by activation of EGFR and subsequent signaling via the ERK1/2-JAK-STAT3 pathway [55]. ET-1-induced arterial constriction requires MMP-dependent shedding of HB-EGF and subsequent EGFR activation with a rapid increase in intracellular Ca2+[56]. Mice deficient in HB-EGF or in EGFR (wa-2) demonstrate a markedly blunted increase in blood pressure in response to ET-1 [57]. Furthermore, the EGFR mediates α-adrenergic vasoconstriction in isolated arteries [58]. As compared to normotensive rats, the expression of HB-EGF processing enzymes is increased in arteries from hypertensive rats, and inhibition of MMPs decreases blood pressure [58]. EGFR signaling also is involved in regulation of sodium reabsorption [59]. These observations suggest a role for EGFR in the regulation of vascular tone and blood pressure.

4.2. Angiogenesis

Limited studies have examined the role of EGFR and its ligands in angiogenesis in the normal vasculature, whereas a large body of literature in the cancer field documents a link between EGFR and vascular endothelial growth factor (VEGF), a well-known initiator of angiogenesis. For example, EGFR inhibition decreases VEGF expression and tumor vascularization [60]. Multiple mechanisms exist whereby EGFR activation leads to VEGF signaling, including activation of PI3K and MAPK pathways and several transcription factors that regulate VEGF transcription [60]. One might speculate that similar mechanisms exist in the setting of remodeling and neovascularization associated with vascular injury. Indeed, there is evidence for increased EGFR phosphorylation in collateral growth in a model of hind limb ischemia [61]. Moreover, treatment of HUVECs in vitro with HB-EGF promotes up regulation of eNOS and release of NO via a PI3K-dependent pathway [52], consistent with a role for HB-EGF in angiogenesis. However, studies using an HB-EGF knockout mouse demonstrate that, while EGFR phosphorylation is decreased in collateral growth in the hind limb ischemia model, there is no difference in arteriogenesis as compared to littermates [61]. Stem cell-based neovascularization following hind limb ischemia can be achieved using stem cells that either express high levels of endogenous EGF or have been stimulated with exogenous EGF [62,63], though the mechanisms are not understood. In cardiac muscle cells, transactivation of EGFR by ET-1 has been shown to induce expression of connective tissue growth factor, which is associated with angiogenesis, in a mechanism that requires activation of ERK and ROS [64]. In a very recent study that was attempting to understand how insulin paradoxically temporally increases retinal edema in diabetes mellitus, it was found that EGFR signaling increases vascular leakage in diabetic mice [65]. Moreover, inhibition of EGFR prevents this effect. In addition, pathologic neovascularization in the retina is abrogated by inhibition of EGFR [66]. Taken together, these data indicate that EGFR contributes to physiologic and pathologic angiogenesis.

4.3. Restenosis

Many of the central processes involved in the dysregulated growth of cancer cells are also present in vascular disease, particularly neointimal hyperplasia associated with vascular injury. In patients, the treatment of arterial stenosis by angioplasty or stent implantation is associated with restenosis. Administration of a blocking antibody to EGFR inhibits VSMC proliferation and intimal hyperplasia following balloon injury in animal models of restenosis [67,68]. Nox1 has been implicated in neointimal hyperplasia [69], and data from our group have identified activation of EGFR in the mechanism of increased Nox1 expression in VSMCs [49]. Consistent with these observations, Nox1 expression in aorta correlates with plasma levels of EGF-like ligands [31]. These data suggest a potential role for EGFR in neointimal hyperplasia.

4.4. Atherosclerosis

Several observations have suggested a potential role for EGFR signaling in atherogenesis. The expression of the EGFR and its ligands (HB-EGF, BTC, and EREG) are elevated in the vascular lesions of humans with atherosclerosis [30,70]. In addition to vascular cells, infiltrating monocytes and macrophages are another important source of EGF-like ligands in atherosclerosis [30]. Furthermore, plasma levels of HB-EGF are increased in patients with coronary artery disease [71] and correlate with serum cholesterol [72]. We have recently extended these findings by examining non-human primates on an atherogenic diet. Phosphorylation of EGFR in the carotid artery and the vascular and plasma levels of EGF-like ligands are increased in monkeys on an atherogenic diet as compared to a normal diet. Interestingly, these changes normalize within 8 months of returning to a normal diet [31]. The increase in circulating EGF-like ligands likely contributes to the enhanced vascular EGFR activation. This mechanism may also be involved in the association between chronic inflammatory diseases and accelerated atherosclerosis. However, to our knowledge, no studies have examined the effects of increased circulating EGF-like ligands in vascular disease.

Another potential mechanism mediating EGFR signaling is related to the finding that the redox state of plasma is more oxidized in patients with risk factors for atherosclerosis [73]. Our data demonstrate that a more oxidized extracellular redox state causes ADAM/MMP-dependent shedding of EGF-like ligands from VSMCs [50]. Consistent with these data, the expression of several ADAMs is increased in atherosclerotic plaques [74]. Despite these clear associations between expression of EGFR and its ligands in atherosclerosis, no studies have addressed whether modulation of EGFR signaling impacts atherogenesis.

4.5. Cardiac Injury and Remodeling

While there is a large body of literature on ErbB family members in the heart, a majority of studies have focused on ErbB2, ErbB4, and neuregulin and not EGFR. For example, dilated cardiomyopathy is associated with inhibition of ErbB2 and ErbB4 signaling, whereas activation of these receptors with neuregulin-1 improves cardiac function [75]. Similar to ErbB2 conditional knockout mice, hearts from HB-EGF null mice exhibit increased chamber size, myofiber hypertrophy, and decreased fractional shortening, signs of severe cardiac dysfunction [27]. It is important to note that the constitutive tyrosine phosphorylation levels of ErbB2 and ErbB4 are reduced in HB-EGF null mice [27]. Decreased survival of cardiomyocytes is one potential cause of the cardiomyopathy in ErbB2 and HB-EGF null mice since partial rescue of ventricular dilation and contractility was observed when the antiapoptotic gene Bcl-xL was overexpressed [76]. ErbB2 transgenic mice display characteristics similar to those found in patients with hypertrophic cardiomyopathy, with susceptibility to adrenergic-induced arrhythmias. Interestingly, the over-expression of ErbB2 induces a concurrent up-regulation of multiple proteins associated with this signaling pathway, including EGFR, ErbB3, ErbB4, PI3K, bcl-2 and multiple protective heat shock proteins. In addition, over expression of ErbB2 causes an anti-apoptotic shift in the ratio of bcl-xS/xL in the heart [77].

ErbB signaling may also have a role in regulating the contractility of the adult heart since ErbB2 and ErbB4 are located in the T-tubule ultrastructural network in cardiomyocytes, the site of excitation-contraction coupling [78]. For example, EGF increases myocardial contractility by elevating cAMP levels in myocytes in a mechanism that requires EGFR tyrosine kinase activity [79,80]. A number of reports have concluded that ERK1/2 and Akt are important for EGFR-mediated cardiomyocyte survival [8183]. Expression of a dominant negative EGFR mutant in cardiomyocytes results in an increase in the left ventricular mass, consistent with cardiac hypertrophy, and a decrease in fractional shortening that could be normalized by cAMP stimulation [84].

Aldosterone causes inflammation and fibrosis of the heart and remodeling of blood vessels [85]. Interestingly, aldosterone increases the expression of EGFR via the interaction of aldosterone-bound mineralocorticoid receptor with the EGFR promoter [86]. Furthermore, several studies have suggested synergy between aldosterone and AngII via crosstalk that involves EGFR [87]. Inhibition of the EGFR attenuates the AngII-mediated synthesis and release of the extracellular matrix protein fibronectin by cardiac fibroblasts [88]. AngII-dependent cardiac hypertrophy requires cardiac EGFR activation [89], and antisense to EGFR decreases left ventricular hypertrophy in young spontaneously hypertensive rats [90]. However, using a cardiomyocyte-specific overexpression of mutant EGFR, it was recently suggested that, although EGFR contributes to AngII-mediated cardiac remodeling, it may not be necessary for the remodeling effects of aldosterone [91]. In addition, GPCRs have been proposed as potential cardiac preconditioning mimetics. Transactivation of EGFR is required for the protective effect of bradykinin on reducing infarct size in a model of rat ischemia reperfusion [92]. Further investigation is required to resolve the mechanistic contribution of EGFR in cardiac remodeling.

4.6. Diabetes Mellitus

Diabetes mellitus increases the risk for multiple cardiovascular complications. Several observations suggest a role for EGFR activation in vascular dysfunction associated with type 1 and type 2 diabetes. EGFR phosphorylation is elevated in the type 2 diabetic mice (db/db) [93]. Inhibition of EGFR signaling normalizes the altered vasoconstrictor and vasodilator responses in streptozocin-induced diabetic rats [94,95] and, in db/db mice, restores eNOS expression, thereby improving both conduit and resistance vessel endothelium-dependent relaxation [93]. Abnormal myogenic tone associated with diabetes is mediated in part via EGFR signaling [96]. In addition, inhibition of EGFR prevents the majority of the changes in gene expression within the rat mesenteric vasculature associated with streptozocin-induced diabetes [97]. These data indicate that activation of EGFR contributes to the vascular dysfunction associated with diabetes.

5. Therapeutic Implications

As we have reviewed herein, there is growing evidence for causal roles for EGFR and its ligands in the development and progression of many cardiovascular abnormalities. Mutations in EGFR have been documented in many cancers and impact response to therapy. However, it is important to note that the majority of these mutations are somatic rather than germline mutations and, to date, no mutations in EGFR have been reported that alter its activity in the cardiovascular system.

Based on the role of EGFR and its ligands in cardiovascular disease, EGFR inhibitors should be explored as a therapeutic strategy. Numerous inhibitors of EGFR family members have been developed for clinical applications in solid tumors. To date, three small molecule tyrosine kinase inhibitors (TKIs, EGFR–gefitinib and erlotinib; EGFR/HER2–lapatinib) and four monoclonal antibodies (mAbs, EGFR–cetuximab and panitumumab; HER2–trastuzumab and pertuxumab) have been FDA-approved for use in breast, colorectal, head and neck, non-small cell lung, and pancreatic cancers. The TKIs are ATP analogs that bind in the ATP binding pocket of the tyrosine kinase domain with high affinity, thereby preventing receptor activation. Due to the fairly distinct structure of the tyrosine kinase domain in EGFR, HER2, and HER4, the TKIs targeting these receptors have little effect on catalytic activity of other tyrosine kinase receptors. All FDA-approved TKIs are reversible inhibitors, though irreversible inhibitors are being tested in clinical trials. The mAbs bind to the extracellular domain to antagonize ligand binding and induce receptor internalization without activating the receptor (i.e., cetuximab) or prevent dimerization (i.e., pertuzumab). In addition, some studies of mAbs (i.e., trastuzumab) have demonstrated additional therapeutic benefit due to antibody-dependent cell-mediated cytotoxicity, a process in which binding of the antibody to target cancer cells elicits an anti-tumor immune response [98].

Highlighting the pivotal role for EGFR family members in cardiovascular homeostasis, the EGFR family targeted therapies are associated with adverse cardiac effects, the most notable of which is cardiotoxicity associated with the HER2 mAb trastuzumab [99]. Toxicity ranges from subclinical abnormalities like asymptomatic decline in ejection fraction to more severe events such as congestive heart failure and acute coronary syndrome [100]. While inhibition of EGFR may produce adverse cardiovascular effects, they are generally manageable [99] and do not necessarily preclude consideration of EGFR inhibitors for the treatment of cardiovascular disorders.

6. Conclusions

The signaling cascades induced by EGFR activation do not differ significantly among cell types in the vasculature and heart. Despite these similarities, we are only beginning to understand the precise contribution of EGFR and its ligands to normal cardiovascular biology and disease pathogenesis. Whole-animal and conditional knockout mice have shed light on the role of EGFR and its ligands on cardiac development, yet one important issue that remains to be addressed is the redundant and differential functions of EGFR, other ErbB family members, and the various EGFR ligands in cardiovascular function. Future studies that use cell-specific and conditional deletion or overexpression of these receptors and ligands are critical to decipher the full web of influence of EGFR family signaling in cardiovascular biology and disease.

Ijms 14 20597f1 200
Figure 1. Epidermal growth factor receptor (EGFR) activation either by ligand binding or by transactivation mechanisms results in induction of several downstream signaling pathways.

Click here to enlarge figure

Figure 1. Epidermal growth factor receptor (EGFR) activation either by ligand binding or by transactivation mechanisms results in induction of several downstream signaling pathways.
Ijms 14 20597f1 1024
Ijms 14 20597f2 200
Figure 2. EGFR and its ligands are implicated in multiple vascular disease states. EGFR acts as a switchboard for signaling many cellular processes involved in vascular disease, including cell proliferation, differentiation, survival, migration, matrix homeostasis, and inflammation. EGFR and its ligands are expressed by VSMCs and ECs as well as inflammatory cells.

Click here to enlarge figure

Figure 2. EGFR and its ligands are implicated in multiple vascular disease states. EGFR acts as a switchboard for signaling many cellular processes involved in vascular disease, including cell proliferation, differentiation, survival, migration, matrix homeostasis, and inflammation. EGFR and its ligands are expressed by VSMCs and ECs as well as inflammatory cells.
Ijms 14 20597f2 1024


This work was supported by Office of Research and Development, Department of Veterans Affairs 1BX001729 and the American Heart Association GRNT12060205 to F.J.M. The funding sources had no role in study design; in the writing of the report; and in the decision to submit the article for publication.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Holbro, T.; Hynes, N.E. ErbB receptors: Directing key signaling networks throughout life. Annu. Rev. Pharmacol. Toxicol 2004, 44, 195–217.
  2. Hackel, P.O.; Zwick, E.; Prenzel, N.; Ullrich, A. Epidermal growth factor receptors: Critical mediators of multiple receptor pathways. Curr. Opin. Cell Biol 1999, 11, 184–189.
  3. Wetzker, R.; Bohmer, F.D. Transactivation joins multiple tracks to the ERK/MAPK cascade. Nat. Rev. Mol. Cell Biol 2003, 4, 651–657.
  4. Prenzel, N.; Zwick, E.; Daub, H.; Leserer, M.; Abraham, R.; Wallasch, C.; Ullrich, A. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 1999, 402, 884–888.
  5. Prenzel, N.; Fischer, O.M.; Streit, S.; Hart, S.; Ullrich, A. The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr. Relat. Cancer 2001, 8, 11–31.
  6. Andreev, J.; Galisteo, M.L.; Kranenburg, O.; Logan, S.K.; Chiu, E.S.; Okigaki, M.; Cary, L.A.; Moolenaar, W.H.; Schlessinger, J, Sr. c and Pyk2 mediate G-protein-coupled receptor activation of epidermal growth factor receptor (EGFR) but are not required for coupling to the mitogen-activated protein (MAP) kinase signaling cascade. J. Biol. Chem 2001, 276, 20130–20135.
  7. Lin, S.Y.; Makino, K.; Xia, W.; Matin, A.; Wen, Y.; Kwong, K.Y.; Bourguignon, L.; Hung, M.C. Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nat. Cell Biol 2001, 3, 802–808.
  8. Liao, H.J.; Carpenter, G. Role of the Sec61 translocon in EGF receptor trafficking to the nucleus and gene expression. Mol. Biol. Cell 2007, 18, 1064–1072.
  9. Liao, H.J.; Carpenter, G. Regulated intramembrane cleavage of the EGF receptor. Traffic 2012, 13, 1106–1112.
  10. Wilken, J.A.; Perez-Torres, M.; Nieves-Alicea, R.; Cora, E.M.; Christensen, T.A.; Baron, A.T.; Maihle, N.J. Shedding of soluble epidermal growth factor receptor (sEGFR) is mediated by a metalloprotease/fibronectin/integrin axis and inhibited by cetuximab. Biochemistry 2013, 52, 4531–4540.
  11. Massague, J.; Pandiella, A. Membrane-anchored growth factors. Annu. Rev. Biochem 1993, 62, 515–541.
  12. Burgess, A.W. Epidermal growth factor and transforming growth factor alpha. Br. Med. Bull 1989, 45, 401–424.
  13. Peschon, J.J.; Slack, J.L.; Reddy, P.; Stocking, K.L.; Sunnarborg, S.W.; Lee, D.C.; Russell, W.E.; Castner, B.J.; Johnson, R.S.; Fitzner, J.N.; et al. An essential role for ectodomain shedding in mammalian development. Science 1998, 282, 1281–1284.
  14. Hinkle, C.L.; Mohan, M.J.; Lin, P.; Yeung, N.; Rasmussen, F.; Milla, M.E.; Moss, M.L. Multiple metalloproteinases process protransforming growth factor-alpha (proTGF-alpha). Biochemistry 2003, 42, 2127–2136.
  15. Yu, W.H.; Woessner, J.F., Jr.; McNeish, J.D.; Stamenkovic, I. CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling. Genes Dev 2002, 16, 307–323.
  16. Suzuki, M.; Raab, G.; Moses, M.A.; Fernandez, C.A.; Klagsbrun, M. Matrix metalloproteinase-3 releases active heparin-binding EGF-like growth factor by cleavage at a specific juxtamembrane site. J. Biol. Chem 1997, 272, 31730–31737.
  17. Miettinen, P.J.; Berger, J.E.; Meneses, J.; Phung, Y.; Pedersen, R.A.; Werb, Z.; Derynck, R. Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature 1995, 376, 337–341.
  18. Sibilia, M.; Wagner, E.F. Strain-dependent epithelial defects in mice lacking the EGF receptor. Science 1995, 269, 234–238.
  19. Threadgill, D.W.; Dlugosz, A.A.; Hansen, L.A.; Tennenbaum, T.; Lichti, U.; Yee, D.; LaMantia, C.; Mourton, T.; Herrup, K.; Harris, R.C.; et al. Targeted disruption of mouse EGF receptor: Effect of genetic background on mutant phenotype. Science 1995, 269, 230–234.
  20. Kornblum, H.I.; Hussain, R.; Wiesen, J.; Miettinen, P.; Zurcher, S.D.; Chow, K.; Derynck, R.; Werb, Z. Abnormal astrocyte development and neuronal death in mice lacking the epidermal growth factor receptor. J. Neurosci. Res 1998, 53, 697–717.
  21. Sibilia, M.; Steinbach, J.P.; Stingl, L.; Aguzzi, A.; Wagner, E.F. A strain-independent postnatal neurodegeneration in mice lacking the EGF receptor. EMBO J 1998, 17, 719–731.
  22. Luetteke, N.C.; Phillips, H.K.; Qiu, T.H.; Copeland, N.G.; Earp, H.S.; Jenkins, N.A.; Lee, D.C. The mouse waved-2 phenotype results from a point mutation in the EGF receptor tyrosine kinase. Genes Dev 1994, 8, 399–413.
  23. Barrick, C.J.; Roberts, R.B.; Rojas, M.; Rajamannan, N.M.; Suitt, C.B.; O’Brien, K.D.; Smyth, S.S.; Threadgill, D.W. Reduced EGFR causes abnormal valvular differentiation leading to calcific aortic stenosis and left ventricular hypertrophy in C57BL/6J but not 129S1/SvImJ mice. Am. J. Physiol. Heart Circ. Physiol 2009, 297, H65–H75.
  24. Gassmann, M.; Casagranda, F.; Orioli, D.; Simon, H.; Lai, C.; Klein, R.; Lemke, G. Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 1995, 378, 390–394.
  25. Lee, K.F.; Simon, H.; Chen, H.; Bates, B.; Hung, M.C.; Hauser, C. Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 1995, 378, 394–398.
  26. McBride, K.L.; Zender, G.A.; Fitzgerald-Butt, S.M.; Seagraves, N.J.; Fernbach, S.D.; Zapata, G.; Lewin, M.; Towbin, J.A.; Belmont, J.W. Association of common variants in ERBB4 with congenital left ventricular outflow tract obstruction defects. Birth Defects Res. A 2011, 91, 162–168.
  27. Iwamoto, R.; Yamazaki, S.; Asakura, M.; Takashima, S.; Hasuwa, H.; Miyado, K.; Adachi, S.; Kitakaze, M.; Hashimoto, K.; Raab, G.; et al. Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function. Proc. Natl. Acad. Sci. USA 2003, 100, 3221–3226.
  28. Hartmann, D.; de Strooper, B.; Serneels, L.; Craessaerts, K.; Herreman, A.; Annaert, W.; Umans, L.; Lubke, T.; Lena Illert, A.; von Figura, K.; Saftig, P. The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts. Hum. Mol. Genet 2002, 11, 2615–2624.
  29. Kato, M.; Inazu, T.; Kawai, Y.; Masamura, K.; Yoshida, M.; Tanaka, N.; Miyamoto, K.; Miyamori, I. Amphiregulin is a potent mitogen for the vascular smooth muscle cell line, A7r5. Biochem. Biophys. Res. Commun 2003, 301, 1109–1115.
  30. Dreux, A.C.; Lamb, D.J.; Modjtahedi, H.; Ferns, G.A. The epidermal growth factor receptors and their family of ligands: Their putative role in atherogenesis. Atherosclerosis 2006, 186, 38–53.
  31. Stanic, B.; Pandey, D.; Fulton, D.J.; Miller, F.J., Jr. Increased epidermal growth factor-like ligands are associated with elevated vascular nicotinamide adenine dinucleotide phosphate oxidase in a primate model of atherosclerosis. Arterioscler. Thromb. Vasc. Biol 2012, 32, 2452–2460.
  32. Gospodarowicz, D.; Hirabayashi, K.; Giguere, L.; Tauber, J.P. Factors controlling the proliferative rate, final cell density, and life span of bovine vascular smooth muscle cells in culture. J. Cell Biol 1981, 89, 568–578.
  33. Schreier, B.; Dohler, M.; Rabe, S.; Schneider, B.; Schwerdt, G.; Ruhs, S.; Sibilia, M.; Gotthardt, M.; Gekle, M.; Grossmann, C. Consequences of epidermal growth factor receptor (ErbB1) loss for vascular smooth muscle cells from mice with targeted deletion of ErbB1. Arterioscler. Thromb. Vasc. Biol 2011, 31, 1643–1652.
  34. Mazak, I.; Fiebeler, A.; Muller, D.N.; Park, J.K.; Shagdarsuren, E.; Lindschau, C.; Dechend, R.; Viedt, C.; Pilz, B.; Haller, H.; et al. Aldosterone potentiates angiotensin II-induced signaling in vascular smooth muscle cells. Circulation 2004, 109, 2792–2800.
  35. Min, L.J.; Mogi, M.; Li, J.M.; Iwanami, J.; Iwai, M.; Horiuchi, M. Aldosterone and angiotensin II synergistically induce mitogenic response in vascular smooth muscle cells. Circ. Res 2005, 97, 434–442.
  36. Berk, B.C.; Brock, T.A.; Webb, R.C.; Taubman, M.B.; Atkinson, W.J.; Gimbrone, M.A., Jr.; Alexander, R.W. Epidermal growth factor, a vascular smooth muscle mitogen, induces rat aortic contraction. J. Clin. Invest 1985, 75, 1083–1086.
  37. Ushio-Fukai, M.; Griendling, K.K.; Becker, P.L.; Hilenski, L.; Halleran, S.; Alexander, R.W. Epidermal growth factor receptor transactivation by angiotensin II requires reactive oxygen species in vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol 2001, 21, 489–495.
  38. Chen, C.H.; Cheng, T.H.; Lin, H.; Shih, N.L.; Chen, Y.L.; Chen, Y.S.; Cheng, C.F.; Lian, W.S.; Meng, T.C.; Chiu, W.T.; et al. Reactive oxygen species generation is involved in epidermal growth factor receptor transactivation through the transient oxidization of src homology 2-containing tyrosine phosphatase in endothelin-1 signaling pathway in rat cardiac fibroblasts. Mol. Pharmacol 2006, 69, 1347–1355.
  39. Yang, C.M.; Lin, M.I.; Hsieh, H.L.; Sun, C.C.; Ma, Y.H.; Hsiao, L.D. Bradykinin-induced p42/p44 MAPK phosphorylation and cell proliferation via Src, EGF receptors, and PI3-K/Akt in vascular smooth muscle cells. J. Cell Physiol 2005, 203, 538–546.
  40. Iwasaki, H.; Eguchi, S.; Marumo, F.; Hirata, Y. Endothelin-1 stimulates DNA synthesis of vascular smooth-muscle cells through transactivation of epidermal growth factor receptor. J. Cardiovasc. Pharmacol 1998, 31, S182–S184.
  41. Kawanabe, Y.; Masaki, T.; Hashimoto, N. Involvement of epidermal growth factor receptor-protein tyrosine kinase transactivation in endothelin-1-induced vascular contraction. J. Neurosurg 2004, 100, 1066–1071.
  42. Kanda, Y.; Mizuno, K.; Kuroki, Y.; Watanabe, Y. Thrombin-induced p38 mitogen-activated protein kinase activation is mediated by epidermal growth factor receptor transactivation pathway. Br. J. Pharmacol 2001, 132, 1657–1664.
  43. Jagadeesha, D.K.; Takapoo, M.; Banfi, B.; Bhalla, R.C.; Miller, F.J., Jr. Nox1 transactivation of epidermal growth factor receptor promotes N-cadherin shedding and smooth muscle cell migration. Cardiovasc. Res 2012, 93, 406–413.
  44. Eguchi, S.; Inagami, T. Signal transduction of angiotensin II type 1 receptor through receptor tyrosine kinase. Regul. Pept 2000, 91, 13–20.
  45. Ohtsu, H.; Dempsey, P.J.; Eguchi, S. ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors. Am. J. Physiol. Cell Physiol 2006, 291, C1–C10.
  46. Seals, D.F.; Courtneidge, S.A. The ADAMs family of metalloproteases: Multidomain proteins with multiple functions. Genes Dev 2003, 17, 7–30.
  47. Van Wart, H.E.; Birkedal-Hansen, H. The cysteine switch: A principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc. Natl. Acad. Sci. USA 1990, 87, 5578–5582.
  48. Takaguri, A.; Shirai, H.; Kimura, K.; Hinoki, A.; Eguchi, K.; Carlile-Klusacek, M.; Yang, B.; Rizzo, V.; Eguchi, S. Caveolin-1 negatively regulates a metalloprotease-dependent epidermal growth factor receptor transactivation by angiotensin II. J. Mol. Cell Cardiol 2011, 50, 545–551.
  49. Miller, F.J., Jr.; Chu, X.; Stanic, B.; Tian, X.; Sharma, R.V.; Davisson, R.L.; Lamb, F.S. A differential role for endocytosis in receptor-mediated activation of Nox1. Antioxid. Redox Signal 2010, 12, 583–593.
  50. Stanic, B.; Katsuyama, M.; Miller, F.J., Jr. An oxidized extracellular oxidation-reduction state increases Nox1 expression and proliferation in vascular smooth muscle cells via epidermal growth factor receptor activation. Arterioscler. Thromb. Vasc. Biol 2010, 30, 2234–2241.
  51. Hsieh, H.L.; Lin, C.C.; Chan, H.J.; Yang, C.M. c-Src-dependent EGF receptor transactivation contributes to ET-1-induced COX-2 expression in brain microvascular endothelial cells. J. Neuroinflammation 2012, 9, 152.
  52. Mehta, V.B.; Zhou, Y.; Radulescu, A.; Besner, G.E. HB-EGF stimulates eNOS expression and nitric oxide production and promotes eNOS dependent angiogenesis. Growth Factors 2008, 26, 301–315.
  53. Zhou, Y.; Brigstock, D.; Besner, G.E. Heparin-binding EGF-like growth factor is a potent dilator of terminal mesenteric arterioles. Microvasc. Res 2009, 78, 78–85.
  54. Schreier, B.; Rabe, S.; Schneider, B.; Bretschneider, M.; Rupp, S.; Ruhs, S.; Neumann, J.; Rueckschloss, U.; Sibilia, M.; Gotthardt, M.; Grossmann, C.; Gekle, M. Loss of epidermal growth factor receptor in vascular smooth muscle cells and cardiomyocytes causes arterial hypotension and cardiac hypertrophy. Hypertension 2013, 61, 333–340.
  55. Amin, A.H.; Abd Elmageed, Z.Y.; Partyka, M.; Matrougui, K. Mechanisms of myogenic tone of coronary arteriole: Role of down stream signaling of the EGFR tyrosine kinase. Microvasc. Res 2011, 81, 135–142.
  56. Chansel, D.; Ciroldi, M.; Vandermeersch, S.; Jackson, L.F.; Gomez, A.M.; Henrion, D.; Lee, D.C.; Coffman, T.M.; Richard, S.; Dussaule, J.C.; Tharaux, P.L. Heparin binding EGF is necessary for vasospastic response to endothelin. FASEB J 2006, 20, 1936–1938.
  57. Flamant, M.; Tharaux, P.L.; Placier, S.; Henrion, D.; Coffman, T.; Chatziantoniou, C.; Dussaule, J.C. Epidermal growth factor receptor trans-activation mediates the tonic and fibrogenic effects of endothelin in the aortic wall of transgenic mice. FASEB J 2003, 17, 327–329.
  58. Hao, L.; Du, M.; Lopez-Campistrous, A.; Fernandez-Patron, C. Agonist-induced activation of matrix metalloproteinase-7 promotes vasoconstriction through the epidermal growth factor-receptor pathway. Circ. Res 2004, 94, 68–76.
  59. Grossmann, C.; Freudinger, R.; Mildenberger, S.; Krug, A.W.; Gekle, M. Evidence for epidermal growth factor receptor as negative-feedback control in aldosterone-induced Na+ reabsorption. Am. J. Physiol. Renal Physiol 2004, 286, F1226–F1231.
  60. Larsen, A.K.; Ouaret, D.; El Ouadrani, K.; Petitprez, A. Targeting EGFR and VEGF(R) pathway cross-talk in tumor survival and angiogenesis. Pharmacol. Ther 2011, 131, 80–90.
  61. Chalothorn, D.; Moore, S.M.; Zhang, H.; Sunnarborg, S.W.; Lee, D.C.; Faber, J.E. Heparin-binding epidermal growth factor-like growth factor, collateral vessel development, and angiogenesis in skeletal muscle ischemia. Arterioscler. Thromb. Vasc. Biol 2005, 25, 1884–1890.
  62. Amin, A.H.; Abd Elmageed, Z.Y.; Nair, D.; Partyka, M.I.; Kadowitz, P.J.; Belmadani, S.; Matrougui, K. Modified multipotent stromal cells with epidermal growth factor restore vasculogenesis and blood flow in ischemic hind-limb of type II diabetic mice. Lab. Invest 2010, 90, 985–996.
  63. Lai, W.H.; Ho, J.C.; Chan, Y.C.; Ng, J.H.; Au, K.W.; Wong, L.Y.; Siu, C.W.; Tse, H.F. Attenuation of hind-limb ischemia in mice with endothelial-like cells derived from different sources of human stem cells. PLoS One 2013, 8, e57876.
  64. Recchia, A.G.; Filice, E.; Pellegrino, D.; Dobrina, A.; Cerra, M.C.; Maggiolini, M. Endothelin-1 induces connective tissue growth factor expression in cardiomyocytes. J. Mol. Cell Cardiol 2009, 46, 352–359.
  65. Sugimoto, M.; Cutler, A.; Shen, B.; Moss, S.E.; Iyengar, S.K.; Klein, R.; Folkman, J.; Anand-Apte, B. Inhibition of EGF signaling protects the diabetic retina from insulin-induced vascular leakage. Am. J. Pathol 2013, 183, 987–995.
  66. Hewing, N.J.; Weskamp, G.; Vermaat, J.; Farage, E.; Glomski, K.; Swendeman, S.; Chan, R.V.; Chiang, M.F.; Khokha, R.; Anand-Apte, B.; Blobel, C.P. Intravitreal injection of TIMP3 or the EGFR inhibitor erlotinib offers protection from oxygen-induced retinopathy in mice. Invest. Ophthalmol. Vis. Sci 2013, 54, 864–870.
  67. Chan, A.K.; Kalmes, A.; Hawkins, S.; Daum, G.; Clowes, A.W. Blockade of the epidermal growth factor receptor decreases intimal hyperplasia in balloon-injured rat carotid artery. J. Vasc. Surg 2003, 37, 644–649.
  68. Shafi, S.; Lamb, D.; Modjtahedi, H.; Ferns, G. Periadventitial delivery of anti-EGF receptor antibody inhibits neointimal macrophage accumulation after angioplasty in a hypercholesterolaemic rabbit. Int. J. Exp. Pathol 2010, 91, 224–234.
  69. Lee, M.Y.; Martin, A.S.; Mehta, P.K.; Dikalova, A.E.; Garrido, A.M.; Datla, S.R.; Lyons, E.; Krause, K.-H.; Banfi, B.; Lambeth, J.D.; et al. Mechanisms of vascular smooth muscle NADPH oxidase 1 (Nox1) contribution to injury-induced neointimal formation. Arterioscler. Thromb. Vasc. Biol 2009, 29, 480–487.
  70. Takahashi, M.; Hayashi, K.; Yoshida, K.; Ohkawa, Y.; Komurasaki, T.; Kitabatake, A.; Ogawa, A.; Nishida, W.; Yano, M.; Monden, M.; Sobue, K. Epiregulin as a major autocrine/paracrine factor released from ERK- and p38MAPK-activated vascular smooth muscle cells. Circulation 2003, 108, 2524–2529.
  71. Matsumoto, S.; Kishida, K.; Shimomura, I.; Maeda, N.; Nagaretani, H.; Matsuda, M.; Nishizawa, H.; Kihara, S.; Funahashi, T.; Matsuzawa, Y.; et al. Increased plasma HB-EGF associated with obesity and coronary artery disease. Biochem. Biophys. Res. Commun 2002, 292, 781–786.
  72. Sanchez-Vizcaino, E.; Vehi, C.; Camprecios, G.; Morcillo, C.; Soley, M.; Ramirez, I. Heparin-binding EGF-like growth factor in human serum. Association with high blood cholesterol and heart hypertrophy. Growth Factors 2009, 28, 98–103.
  73. Jones, D.P. Redefining oxidative stress. Antioxid. Redox Signal 2006, 8, 1865–1879.
  74. Van der Vorst, E.P.; Keijbeck, A.A.; de Winther, M.P.; Donners, M.M. A disintegrin and metalloproteases: Molecular scissors in angiogenesis, inflammation and atherosclerosis. Atherosclerosis 2012, 224, 302–308.
  75. Liu, X.; Gu, X.; Li, Z.; Li, X.; Li, H.; Chang, J.; Chen, P.; Jin, J.; Xi, B.; Chen, D.; et al. Neuregulin-1/erbB-activation improves cardiac function and survival in models of ischemic, dilated, and viral cardiomyopathy. J. Am. Coll. Cardiol 2006, 48, 1438–1447.
  76. Crone, S.A.; Zhao, Y.Y.; Fan, L.; Gu, Y.; Minamisawa, S.; Liu, Y.; Peterson, K.L.; Chen, J.; Kahn, R.; Condorelli, G.; et al. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat. Med 2002, 8, 459–465.
  77. Sysa-Shah, P.; Xu, Y.; Guo, X.; Belmonte, F.; Kang, B.; Bedja, D.; Pin, S.; Tsuchiya, N.; Gabrielson, K. Cardiac-specific over-expression of epidermal growth factor receptor 2 (ErbB2) induces pro-survival pathways and hypertrophic cardiomyopathy in mice. PLoS One 2012, 7, e42805.
  78. Ozcelik, C.; Erdmann, B.; Pilz, B.; Wettschureck, N.; Britsch, S.; Hubner, N.; Chien, K.R.; Birchmeier, C.; Garratt, A.N. Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy. Proc. Natl. Acad. Sci. USA 2002, 99, 8880–8885.
  79. Nair, B.G.; Rashed, H.M.; Patel, T.B. Epidermal growth factor produces inotropic and chronotropic effects in rat hearts by increasing cyclic AMP accumulation. Growth Factors 1993, 8, 41–48.
  80. Patel, T.B. Single transmembrane spanning heterotrimeric g protein-coupled receptors and their signaling cascades. Pharmacol. Rev 2004, 56, 371–385.
  81. Forster, K.; Kuno, A.; Solenkova, N.; Felix, S.B.; Krieg, T. The delta-opioid receptor agonist DADLE at reperfusion protects the heart through activation of pro-survival kinases via EGF receptor transactivation. Am. J. Physiol. Heart Circ. Physiol 2007, 293, H1604–1608.
  82. Fujio, Y.; Nguyen, T.; Wencker, D.; Kitsis, R.N.; Walsh, K. Akt promotes survival of cardiomyocytes in vitro and protects against ischemia-reperfusion injury in mouse heart. Circulation 2000, 101, 660–667.
  83. Matsui, T.; Nagoshi, T.; Rosenzweig, A. Akt and PI 3-kinase signaling in cardiomyocyte hypertrophy and survival. Cell Cycle 2003, 2, 220–223.
  84. Rajagopalan, V.; Zucker, I.H.; Jones, J.A.; Carlson, M.; Ma, Y.J. Cardiac ErbB-1/ErbB-2 mutant expression in young adult mice leads to cardiac dysfunction. Am. J. Physiol. Heart Circ. Physiol 2008, 295, H543–H554.
  85. Brown, N.J. Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis. Nat. Rev. Nephrol 2013, 9, 459–469.
  86. Grossmann, C.; Krug, A.W.; Freudinger, R.; Mildenberger, S.; Voelker, K.; Gekle, M. Aldosterone-induced EGFR expression: Interaction between the human mineralocorticoid receptor and the human EGFR promoter. Am. J. Physiol. Endocrinol. Metab 2007, 292, E1790–E1800.
  87. Montezano, A.C.; Callera, G.E.; Yogi, A.; He, Y.; Tostes, R.C.; He, G.; Schiffrin, E.L.; Touyz, R.M. Aldosterone and angiotensin II synergistically stimulate migration in vascular smooth muscle cells through c-Src-regulated redox-sensitive RhoA pathways. Arterioscler. Thromb. Vasc. Biol 2008, 28, 1511–1518.
  88. Moriguchi, Y.; Matsubara, H.; Mori, Y.; Murasawa, S.; Masaki, H.; Maruyama, K.; Tsutsumi, Y.; Shibasaki, Y.; Tanaka, Y.; Nakajima, T.; et al. Angiotensin II-induced transactivation of epidermal growth factor receptor regulates fibronectin and transforming growth factor-beta synthesis via transcriptional and posttranscriptional mechanisms. Circ. Res 1999, 84, 1073–1084.
  89. Zhai, P.; Galeotti, J.; Liu, J.; Holle, E.; Yu, X.; Wagner, T.; Sadoshima, J. An angiotensin II type 1 receptor mutant lacking epidermal growth factor receptor transactivation does not induce angiotensin II-mediated cardiac hypertrophy. Circ. Res 2006, 99, 528–536.
  90. Kagiyama, S.; Qian, K.; Kagiyama, T.; Phillips, M.I. Antisense to epidermal growth factor receptor prevents the development of left ventricular hypertrophy. Hypertension 2003, 41, 824–829.
  91. Messaoudi, S.; Zhang, A.D.; Griol-Charhbili, V.; Escoubet, B.; Sadoshima, J.; Farman, N.; Jaisser, F. The epidermal growth factor receptor is involved in angiotensin II but not aldosterone/salt-induced cardiac remodelling. PLoS One 2012, 7, e30156.
  92. Methner, C.; Donat, U.; Felix, S.B.; Krieg, T. Cardioprotection of bradykinin at reperfusion involves transactivation of the epidermal growth factor receptor via matrix metalloproteinase-8. Acta Physiol. (Oxf) 2009, 197, 265–271.
  93. Belmadani, S.; Palen, D.I.; Gonzalez-Villalobos, R.A.; Boulares, H.A.; Matrougui, K. Elevated epidermal growth factor receptor phosphorylation induces resistance artery dysfunction in diabetic db/db mice. Diabetes 2008, 57, 1629–1637.
  94. Benter, I.F.; Yousif, M.H.; Griffiths, S.M.; Benboubetra, M.; Akhtar, S. Epidermal growth factor receptor tyrosine kinase-mediated signalling contributes to diabetes-induced vascular dysfunction in the mesenteric bed. Br. J. Pharmacol 2005, 145, 829–836.
  95. Yousif, M.H.; Benter, I.F.; Akhtar, S. The role of tyrosine kinase-mediated pathways in diabetes-induced alterations in responsiveness of rat carotid artery. Auton. Autacoid Pharmacol 2005, 25, 69–78.
  96. Matrougui, K. Diabetes and microvascular pathophysiology: Role of epidermal growth factor receptor tyrosine kinase. Diabetes Metab. Res. Rev 2010, 26, 13–16.
  97. Benter, I.F.; Benboubetra, M.; Hollins, A.J.; Yousif, M.H.; Canatan, H.; Akhtar, S. Early inhibition of EGFR signaling prevents diabetes-induced up-regulation of multiple gene pathways in the mesenteric vasculature. Vascul. Pharmacol 2009, 51, 236–245.
  98. Clynes, R.A.; Towers, T.L.; Presta, L.G.; Ravetch, J.V. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat. Med 2000, 6, 443–446.
  99. Di Cosimo, S. Heart to heart with trastuzumab: A review on cardiac toxicity. Target. Oncol 2011, 6, 189–195.
  100. Orphanos, G.S.; Ioannidis, G.N.; Ardavanis, A.G. Cardiotoxicity induced by tyrosine kinase inhibitors. Acta Oncol 2009, 48, 964–970.
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert