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Understanding Angiotensin II Type 1 Receptor Signaling in Vascular Pathophysiology

Originally published 2018;71:804–810

Angiotensin II is the most important endocrine ligand in the renin–angiotensin system (RAS), contributing to the development of several cardiovascular diseases including hypertension.1 Angiotensin II mediates its signal transduction and functions via the angiotensin II receptors.2 Historically, the presence of 2 subtypes of angiotensin II receptors were pharmacologically recognized based on the sensitivity to the first orally active nonpeptide angiotensin II receptor antagonist, losartan. The losartan-sensitive receptor was termed AT1 (angiotensin II receptor type 1) receptor. It was assumed to be a heterotrimeric GPCR (G protein–coupled receptor) because it generates inositol triphosphate and diacylglycerol, leading to intracellular Ca2+ elevation and protein kinase C activation, respectively. Most known physiological and pathophysiological functions of angiotensin II, including stimulation of vasoconstriction and salt and water reabsorption, are mediated through the AT1 receptor. The losartan-insensitive receptor was termed AT2 receptor, whereas its G protein coupling remains unclear.1,3,4 In 1991, 2 research groups in the United States independently isolated cDNA (termed AGTR1) encoding the mammalian AT1 receptor.5,6 Subsequently, rat AT2 receptor cDNA (AGTR2) was cloned in 1993.7,8 This pioneer work revealed complete amino acid sequences of the angiotensin II receptor subtypes belonging to the 7-transmembrane GPCR superfamily. In the early 1990s, several studies reported that AT1 receptor elicits tyrosine phosphorylation of multiple proteins and activation of MAPK (mitogen-activated protein kinase; eg, p42/p44 MAPK)/ERK (extracellular signal–regulated kinase; eg, ERK1/2) in various cell types including vascular smooth muscle cells (VSMC). The early 1990s also saw the establishment of the concept that angiotensin II via the AT1 receptor has a direct action on cardiac myocytes, fibroblasts, and VSMCs causing hypertrophic and fibrotic cardiovascular remodeling.9,10 The cardiovascular remodeling caused by angiotensin II seemed to be at least partially independent of the hypertensive action of angiotensin II.11 These findings lead to the identification of common signaling mechanisms shared by AT1 receptor and a growth factor receptor that has an intrinsic tyrosine kinase activity.1215 Interestingly, AT1 receptor can be activated by mechanical stretch contributing to cardiac hypertrophy.16,17 The mechanosensor concept of the AT1 receptor has been expanded to mediate myogenic vasoconstriction.1820 Another key discovery from the early 1990s is NAD(P)H (nicotinamide adenine dinucleotide phosphate) oxidase–dependent reactive oxygen species (ROS) generation through the AT1 receptor activation in VSMC.21 This finding led to a major (yet controversial) concept that ROS mediate cardiovascular pathophysiology including those involving the RAS. The finding was also significant because it is an important foundation for the well-acknowledged concept established in the late 1990s that angiotensin II acts as a proinflammatory cytokine via the AT1 receptor.22 The basic understanding remains solid and unchanged that the AT1 receptor signaling contributes to hypertension and various cardiovascular complications via activation of protein kinases, generation of ROS, and subsequent induction of remodeling and inflammation.2,23 However, there has been astonishing progress elucidating various novel components and pathways in the angiotensin II/AT1 receptor signal transduction for the past 2 decades. AT1 receptor interacts and signals with G proteins and β-arrestin. In addition, AT1 receptor communicates with growing numbers of AT1 receptor–interacting proteins including other GPCRs (heterodimer formation). AT1 receptor seems to activate several new signaling cascades including the Wnt/β-catenin pathway, Notch pathway, and Hippo pathways. Moreover, AT1 receptor mediates additional posttranslational protein modification including acetylation/deacetylation, S-nitrosylation, O-GlcNAcylation, and SUMOylation (small ubiquitin-like modifier) (which are recently reviewed by Kawai et al2). Crystal structures of the AT1 and AT2 receptors have also been recently demonstrated.24,25 However, further research is desired regarding the physiological and pathophysiological roles of these new components and signaling pathways. Here, based on the 2017 Lewis K. Dahl Memorial Lecture, we will describe noteworthy recent concepts of the AT1 receptor signal transduction in mediating vascular pathophysiology. We will also discuss controversies, limitations, and future directions of the AT1 receptor research.

Transactivation of Growth Factor Receptor via ADAM17

It has been demonstrated that angiotensin II activates ERK1/2 via AT1 receptor–mediated transactivation of EGFR (epidermal growth factor receptor) in VSMC in vitro.26 The EGFR transactivation also mediates activation of other downstream kinases, including Akt, p70 S6 kinase, and p38 MAPK, and subsequent hypertrophic responses in VSMC2730 (Figure 1). Note that there are many other classical and novel pathways shown to potentially mediate vascular remodeling in vivo.31 Moreover, although the EGFR transactivation cascade is well acknowledged in VSMCs, whether it has any significance in vascular pathophysiology linked to angiotensin II had not been studied. Recently, our group was able to demonstrate the critical roles the cascade play in angiotensin II–induced hypertensive cardiovascular remodeling.

Figure 1.

Figure 1. Signal transduction mechanism of EGFR (epidermal growth factor receptor) transactivation by angiotensin II (AngII) in vascular smooth muscle cells leading to vascular remodeling. Please note that in addition to this cascade, both classical and novel pathways have been shown to contribute to AngII-mediated vascular remodeling (reviewed in detail recently in the study by Forrester et al31). ADAM17 indicates a disintegrin and metalloprotease 17; AT1R, angiotensin receptor type 1; Cav1, caveolin 1; ERK, extracellular signal–regulated kinase; HB-EGF, heparin-binding EGF-like growth factor; PI3K, phosphoinositide 3-kinase; p70S6K, p70 S6 kinase; PTK, protein tyrosine kinase; and ROS, reactive oxygen species.

On 2-week angiotensin II infusion in mice, activation of EGFR is mainly observed in coronary arteries in the cardiac section. Erlotinib is a clinically used selective EGF receptor kinase inhibitor. Treatment with erlotinib markedly attenuated vascular EGFR activation, vascular medial hypertrophy, and perivascular fibrosis induced by angiotensin II infusion, whereas angiotensin II–induced hypertension was unaltered. Interestingly, angiotensin II–induced cardiac hypertrophy was also prevented by the EGFR inhibitor.32 These data suggest that vascular EGFR transactivation mediate cardiovascular remodeling induced by angiotensin II independently of hypertension. In addition, erlotinib prevented development of abdominal aortic aneurysm induced by cotreatment of angiotensin II and a lysyl oxidase inhibitor, β-aminopropionitrile.33 Others also demonstrated that in EGFR-inactivated mutant mice, angiotensin II–induced cerebral arteriolar hypertrophy but not hypertension was attenuated.34 In smooth muscle–targeted and inducible EGFR silencing mice, vascular hypertrophy and fibrosis induced by angiotensin II infusion were also attenuated, and development of hypertension was partially inhibited. However, angiotensin II–induced cardiac hypertrophy was not prevented.35 Taken together, these data suggest that EGFR transactivation is critical for angiotensin II–mediated cardiovascular complications and that distinct cell types including VSMC and cardiac myocytes may be involved in the EGFR-dependent pathophysiology.

In vitro studies have demonstrated that a metalloprotease, ADAM17 (a disintegrin and metalloprotease 17 ), mediates angiotensin II–induced EGFR transactivation via generation of mature form of heparin-binding EGF-like growth factor.36,37 AT1 receptor activates ADAM17 via Tyr702 phosphorylation through unidentified kinase.38 Src family kinase is the potential candidate because it phosphorylates and activates ADAM17 in response to mechanical stretch in rat myoblasts.39 In addition, several Ser/Thr kinases are implicated in ADAM17 activation in other cell systems.40 We have used SM22α (smooth muscle 22 α)-mediated conditional ADAM17-knockout mice to ask what role VSMC ADAM17 plays in hypertension and associated cardiovascular remodeling induced by angiotensin II. Compared with wild-type littermate control mice, vascular hypertrophy, perivascular fibrosis, and cardiac hypertrophy but not hypertension induced by angiotensin II infusion were blunted in the ADAM17-silenced mice. The phenotype is associated with inhibition of vascular EGFR activation. Systemic ADAM17 inhibition by neutralizing antibody also attenuated angiotensin II–induced cardiovascular remodeling but not hypertension in wild-type mice.41 In addition, development of abdominal aortic aneurysm induced by angiotensin II plus β-aminopropionitrile was also blunted in VSMC ADAM17-silenced mice or wild-type mice treated with ADAM17 antibody.42 Although SM22α-mediated ADAM17 knockdown could partially reduce cardiac myocyte ADAM17 expression,41 others have reported that angiotensin II–induced cardiac hypertrophy was not altered in cardiomyocyte-targeted ADAM17-silenced mice.43 These data further support the concept that the VSMC ADAM17/EGFR transactivation mainly mediates cardiovascular pathology including cardiac hypertrophy induced by angiotensin II.

It should be noted that ADAM17 has many other substrates beside EGFR ligands, including TNFα (tumor necrosis factor α).44 In TNFα-knockout mice, angiotensin II–induced hypertension and cardiac hypertrophy were blunted.45 Transplant experiment with TNFα-knockout mice suggests a partial involvement of TNFα produced in kidney in angiotensin II–induced hypertension.46 Smooth muscle–derived TNFα has been shown to positively contribute to blood pressure responses.47 Another important substrate for ADAM17 is angiotensin-converting enzyme 2 (ACE2). ACE2 cleavage by ADAM17 inactivates ACE2, leading to reduced Ang (1–7) generation and enhanced angiotensin II retention. This concept has been shown to be involved in DOCA (deoxycorticosterone acetate)-salt–induced neurogenic hypertension.48 Subsequent study demonstrated neuronal AT1 receptor mediating the ADAM17-dependent ACE2 inactivation.49 Therefore, in addition to EGFR transactivation, it is important to further investigate the potential participation of TNFα generation and ACE2 inactivation as consequences of ADAM17 activation, leading to hypertension, cardiovascular remodeling, and other types of pathophysiology associated with enhancement of the RAS (Figure 2).

Figure 2.

Figure 2. Potential roles of ADAM17 (a disintegrin and metalloprotease 17) activation in cardiovascular pathophysiology. In addition to EGFR (epidermal growth factor receptor) transactivation, ADAM17 may contribute to endothelial dysfunction and insulin resistance by producing TNFα (tumor necrosis factor α) and inhibiting angiotensin-converting enzyme 2 (ACE2). Ang indicates angiotensin; AT1R, angiotensin receptor type 1; HB-EGF, heparin-binding EGF-like growth factor; and TACE, tumor necrosis factor-α converting enzyme.

Involvement of Caveolin 1 in Angiotensin II–Induced Vascular Remodeling

Caveolae are a specific type of small lipid raft at the plasma membrane and serve as important signal transduction platforms.50 The roles of Cav1 (caveolin 1), a major component protein in caveolae in AT1 receptor signal transduction, have been extensively studied.51 However, limited information has been available on the role of Cav1−mediated angiotensin II signaling in vascular pathophysiology. It has been shown that in Cav1+/− mice, angiotensin II–induced hypertension and decline in NO were partially blunted.52 We have recently examined the involvement of Cav1 in angiotensin II–induced vascular remodeling with Cav1-knockout (Cav1−/−) mice. In Cav1−/− mice, angiotensin II infusion causes hypertension and cardiac hypertrophy similar to the control Cav1+/+ mice. However, angiotensin II–induced vascular hypertrophy and perivascular fibrosis are attenuated in Cav1−/− mice. Protection of vascular remodeling seen in Cav1−/− mice may involve 2 mechanisms according to our in vitro analyses. Cav1 silencing in VSMC attenuated ADAM17 activation, EGFR transactivation, protein synthesis, and collagen synthesis induced by angiotensin II. In addition, Cav1 silencing in endothelial cells prevented induction of vascular endothelial cell adhesion molecule and leukocyte adhesion induced by TNFα.53 We also reported that Cav1-knockout mice were protected from abdominal aortic aneurysm formation induced by angiotensin II, which was associated with reduced inflammatory cytokines and oxidative stress.54 However, several problematic baseline phenotypes are also associated with Cav1−/− mice, including cardiac hypertrophy and pulmonary hypertension.50 Further experiments such as those with cell-type–specific knockout mice are needed before considering any intervention toward Cav1 function.

Endoplasmic Reticulum Stress and Cardiovascular Remodeling

Endoplasmic reticulum (ER) stress is caused by adaptive responses to an excess of misfolded proteins leading to unfolded protein response (UPR). UPR mediates specific signaling pathways, which leads to induction of protein chaperones and attenuation of protein synthesis to reduce misfolded proteins. Sustained ER stress also activates c-Jun N-terminal kinase and nuclear factor-kB causing inflammatory responses. Several disease conditions including those occurring in the cardiovascular system are associated with enhancement of ER stress.55 It has been demonstrated that angiotensin II stimulation causes ER stress/UPR in the target organs including vasculature, heart, and brain.5658 CHOP (CCAAT-enhancer–binding protein homologous protein) is a critical transcriptional factor induced by UPR. CHOP−/− mice are protected from angiotensin II–induced hypertension and cardiovascular pathology.59 Our investigation has demonstrated that angiotensin II–mediated ER stress responses are attenuated if the Cav1/ADAM17/EGFR pathway is inhibited pharmacologically and genetically.32,33,41,42 One potential interpretation is that ER stress causes ADAM17 gene induction and enhances EGFR transactivation as a positive feedback mechanism, where inhibition of either ER stress or the transactivation cascade results in suppression of vascular remodeling induced by angiotensin II.32 Alternatively, suppression of protein synthesis and hypertrophic/fibrotic remodeling reduce the rate of protein misfolding.41 In addition, whether the UPR in response to angiotensin II stimulation is sufficient to attenuate misfolding to maintain protein homeostasis (proteostasis) remains unknown because of a lack of study to directly evaluate protein misfolding. It has been well documented that imbalance among protein folding, UPR, and clearance of misfolded proteins by proteasome pathway or autophagy lead to aggregation of specific sets of proteins causing neurodegenerative diseases. Enhancement of protein aggregates were shown in mice hearts infused with angiotensin II, as well as aged mouse hearts. Nearly a 100 proteins are identified as commonly enriched aggregated proteins.60 It is interesting to speculate that these proteins cause specific proteotoxicity and protein aggregate responses, thus enhancing cardiovascular pathophysiology induced by angiotensin II.

Mitochondrial Signaling of Angiotensin II

Because of its significant contribution to mitochondrial ROS production, angiotensin II–induced mitochondrial dysfunction has been strongly implicated in cardiovascular diseases, metabolic diseases, and aging.61,62 Indeed, inhibition of mitochondrial ROS can attenuate vascular dysfunction and hypertension induced by angiotensin II.63,64 Moreover, angiotensin II–infused mice showed cardiac hypertrophy and diastolic dysfunction associated with reduced cardiac ATP production and glucose oxidation, suggesting a role for angiotensin II signal transduction in mitochondrial dysfunction.65 However, mitochondrial targeted treatment, such as antioxidant peptide or mitochondrial catalase transgene, has no effect on angiotensin II–induced hypertension, whereas these interventions can inhibit cardiac hypertrophy.66,67 Regarding the molecular mechanism by which angiotensin II increases mitochondrial ROS, the contribution of Nox2 (NADPH oxidase)-derived cytosolic ROS has been demonstrated.64 In addition, angiotensin II has been shown to inhibit mitochondrial Sirt3 (sirtuin 3) and SOD2 (superoxide dismutase 2) via S-glutathionylation and acetylation, respectively, thus enhancing mitochondrial ROS generation.68 There are a few reports available on the relationship between angiotensin II pathophysiology and mitophagy. An E3 ubiquitin ligase Atg5 (autophagy protein 5) mediates formation of autophagosomes and autophagy. Angiotensin II increases cardiac Atg5 expression, autophagy, and mitophagy in infiltrated macrophages. In Atg5+/− mice, reduction in macrophage mitophagy is associated with enhancement of cardiac hypertrophy and oxidative stress.69 However, in swine model of renovascular hypertension, AT1 receptor blocker attenuated myocardial mitophagy and increased mitochondrial biogenesis.70

Recent studies also demonstrated that angiotensin II regulates mitochondrial morphology. Mitochondrial fission and fusion are key regulatory mechanisms required for mitochondrial homeostasis and quality control under stress. Accumulating evidence suggest the causal relationship between mitochondrial fragmentation/fission and cardiovascular/metabolic diseases. Mitochondrial fission and fusion are regulated by multiple distinct proteins distributed in cytosol, ER, and mitochondrial outer and inner membranes, of which GTPases, Drp1 (dynamin-related protein 1), and mitofusion 1/2 are central mediators of fission and fusion.71 In cultured VSMC and neuronal cell line SH-SY5Y, angiotensin II stimulation caused mitochondrial fission, which was associated with Drp1 Ser616 phosphorylation.72,73 Moreover, pharmacological inhibition of Drp1 by mdivi1 attenuated angiotensin II–induced mitochondrial ROS production and VSMC proliferation.73 However, it should be noted that mdivi1 is known to inhibit mitochondrial respiration at complex I and modulate ROS production.74

During the lecture, our unpublished data using both pharmacological and genetic manipulations including those obtained with conditional knockout mice were presented. These data support 2 novel signal transduction concepts regarding the mitochondrial dynamics dictating vascular pathophysiology induced by angiotensin II or TNFα. (1) In VSMCs in vitro and in vivo, angiotensin II activation of AT1 receptor causes mitochondrial fragmentation via the EGFR transactivation. Mitochondrial fission seems to be an essential step for cardiovascular remodeling (but not hypertension) induced by angiotensin II. (2) In endothelial cells in vitro and in vivo, TNFα induces mitochondrial fragmentation via a mechanism distinct from EGFR transactivation. Endothelial mitochondrial fragmentation significantly influences TNFα signal transduction. Moreover, inhibition of mitochondrial fragmentation prevents inflammatory responses induced by TNFα infusion in mice including leukocyte adhesion. Further research is warranted to answer several fundamental questions. Why do vascular pathogens cause mitochondrial fission and what is the consequence to mitochondrial homeostasis and cellular phenotype in cardiovascular diseases? What is the essential forward-grade signaling mechanism used by the receptors that cause vascular mitochondrial fragmentation? Finally, we need to explore the other essential retrograde signaling mechanism by which mitochondrial fragmentation mediate vascular remodeling and inflammation.

Cell-Type–Specific AT1 Receptor Signal Transduction

Although the literature presented here strongly suggests that VSMC (and perhaps partially via endothelial) AT1 receptor signaling mechanisms mediate angiotensin II pathophysiology in the vasculature including hypertension and vascular remodeling, there are noteworthy findings challenging these concepts. We are aware of the accumulating findings suggesting the importance of several distinct immune cell populations in mediating hypertension and endothelial dysfunction in response to angiotensin II.75 However, caution is required when interpreting the findings in this field.76 Many of the strategies used manipulate a specific subset of immune cells by removing their presence in mice. As such, it is difficult to specify whether the outcomes are attributable to the initiation of angiotensin II signal transduction in the immune cell, whether the immune cell’s function lay downstream of AT1 receptor signal transduction originally elicited in other cell types, or whether removing the specific immune cell type is affecting the phenotype independently of the RAS. Deletion of AT1 receptor in bone marrow–derived cells augmented hypertension, renal inflammation, and injury in mice.77 Bone marrow AT1 receptor seems dispensable for angiotensin II–induced enhancement of atherosclerosis in apoE (apolipoprotein E)−/− mice.78 A few studies are available using immune cell–targeted conditional AT1 receptor–knockout mice. In T-cell AT1 receptor–knockout mouse, no alteration was detected in hypertension induced by angiotensin II. Moreover, angiotensin II–induced renal injury was enhanced in the knockout mice.79 Macrophage AT1 receptor deletion also indicate the role of macrophage AT1 receptor in renal protection.80 These data, thus, challenge the concept that inactivation of the AT1 receptor on inflammatory T cell or macrophage is protective against hypertension and end-organ damage. The findings also indicate that although T cells and macrophages enhance angiotensin II causing hypertension and end-organ damage, these actions are independent of immune cell RAS and likely regulated through the peripheral AT1 receptor. However, additional investigation is needed to explore the protective AT1 receptor signal transduction in the immune cells.

Conditional AT1 receptor–knockout mice have also been used to study the requirement of AT1 receptor in VSMC, endothelial cell, and fibroblast to mediate hypertension and vascular remodeling (Table). SM22α-Cre deletion of VSMC AT1, Tie2-Cre deletion of endothelial (and hematopoietic) AT1, or Eno2-Cre deletion of neuronal AT1 did not alter hypertension or vascular medial hypertrophy induced by angiotensin II infusion. In contrast, S100A4-Cre deletion of fibroblast AT1 attenuated vascular hypertrophy but not hypertension induced by angiotensin II.81 However, there is a concern in the interpretation of these data. Although these findings confirm no alteration of hypertension by transgenic SM22α-Cre deletion of VSMC AT1 in angiotensin II–induced hypertension,82 more effective silencing of AT1 receptor using Cre that is regulated by endogenous SM22α (knock-in) shows significant reduction in hypertension induced by angiotensin II infusion.83 However, whether angiotensin II–induced vascular remodeling is attenuated in the mice remains to be studied. Expression of S100A4 in VSMC has been demonstrated.84 Our mass spectrometry analysis of cultured rat VSMC lysates detected protein fragments derived from S100A4 (unpublished observation), thus Cre under control of S100A4 promoter may delete smooth muscle AT1 receptors in addition to those on fibroblasts. In relation to these issues (insufficiency and nonspecific targeting), a critical limitation common in these studies are lack of confirmation of AT1 receptor protein silencing in the target cells/tissues. This is because reliable AT1 receptor antibody has not yet been available.85,86 Therefore, further effort is desired to specify AT1 receptor–expressing cell types involved in angiotensin II–induced cardiovascular pathophysiology.

Table. Phenotype of Conditional AT1 Receptor–Knockout Mice Infused With AngII

Smooth muscleKI SM22αHypertension ↓Sparks et al83
Smooth muscleSM22αHypertension ↔; vascular hypertrophy ↔Poduri et al81; Sparks et al82
Endothelial cellsTie2Hypertension ↔; vascular hypertrophy ↔Poduri et al81
NeuronsEno2Hypertension ↔; vascular hypertrophy ↔Poduri et al81
FibroblastsS100A4Hypertension ↔; vascular hypertrophy ↓Poduri et al81
T lymphocytesCD4Hypertension ↔; kidney injury ↑Zhang et al79
MacrophagesLysMHypertension ↔; kidney injury ↑Zhang et al80

AT indicates angiotensin type 1; AngII, angiotensin II; CD4, cluster of differentiation 4; Eno2, enolase 2; KI, knock-in; LysM, lysozyme M; S100A4, S100 calcium-binding protein A4; SM22α, smooth muscle 22 α; and Tie2, tyrosine kinase with immunoglobulin like and EGF like domains 1.


Here, we summarized the noteworthy novel concepts and progresses in AT1 receptor signal transduction in mediating cardiovascular pathophysiology. The AT1 receptor signal transduction seems to remain a central component in cardiovascular pathophysiology. To conquer cardiovascular complications and improve the prognoses of hypertensive patients, we have to further clarify the complexity of the AT1 signal transduction. Better molecular tools should be developed, and additional effort is required to answer cell/tissue-type–specific roles that AT1 receptor plays in cardiovascular and metabolic diseases. This seems particularly important in cardiac myocytes, fibroblasts, adipocytes, and immune cell subsets. Organelle signal communication, such as those involving ER, mitochondria, and exosomes,87 and balance among protein synthesis, misfolding, aggregation and the proteotoxicity are important questions to ask for their relevance in angiotensin II pathophysiology. We also expect that unbiased system biology and bioinformatics approaches will further shed light on previously unrecognized AT1 receptor signal transduction for the next decade. Finally, we strongly hope that this article helps the researcher to further explore novel molecular mechanisms that RAS play in cardiovascular diseases and that these studies will lead to a remarkable translation into effective therapies.


Correspondence to Satoru Eguchi, Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, 3500 N Broad St, Philadelphia, PA 19140. E-mail


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