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British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 2017 May 10;175(8):1354–1361. doi: 10.1111/bph.13806

The role of Hippo/yes‐associated protein signalling in vascular remodelling associated with cardiovascular disease

Jinlong He 1,2, Qiankun Bao 1, Meng Yan 1, Jing Liang 1, Yi Zhu 1, Chunjiong Wang 1,✉, Ding Ai 1,2,✉
PMCID: PMC5866970  PMID: 28369744

Abstract

Vascular remodelling is a vital process of a wide range of cardiovascular diseases and represents the altered structure and arrangement of blood vessels. The Hippo pathway controls organ size by regulating cell survival, proliferation and apoptosis. Yes‐associated protein (YAP), a transcription coactivator, is a downstream effector of the Hippo pathway. There is growing evidence for the importance of the Hippo/YAP pathway in vascular‐remodelling and related cardiovascular diseases. The Hippo/YAP pathway alters extracellular matrix production or degradation and the growth, death and migration of vascular smooth muscle cells and endothelial cells, which contributes to vascular remodelling in cardiovascular diseases such as pulmonary hypertension, atherosclerosis, restenosis, aortic aneurysms and angiogenesis. In this review, we summarize and discuss recent findings about the roles and mechanisms of Hippo/YAP signalling in vascular remodelling and related conditions.

Linked Articles

This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc

Abbreviations

CVD

cardiovascular disease

EC

endothelial cell

ECM

extracellular matrix

ILK1

integrin‐linked kinase 1

LATS

large tumour suppressor

MST

mammalian STE20‐like protein kinase

TAZ

transcriptional coactivator with PDZ‐binding motif

TEAD

transcriptional enhancer associate domain

VSMC

vascular smooth muscle cell

YAP

Yes‐associated protein

Introduction

According to the American Heart Association, although the death rates from cardiovascular diseases (CVDs) have declined recently, these diseases remain the leading cause of morbidity and mortality in developing countries (Roger et al., 2011). Vascular remodelling is an active process of structural alteration that involves changes in cell growth, cell death, cell migration and production or degradation of extracellular matrix (ECM). It is a vital process of a wide range of CVDs including atherosclerosis, hypertension, pulmonary hypertension, aneurysm, restenosis after angioplasty and stenosis of vein bypass grafting (Gibbons and Dzau, 1994). Therefore, therapeutic strategies targeting vascular remodelling have important clinical significance.

The Hippo pathway, discovered in Drosophila, controls organ size by regulating cell survival, proliferation and apoptosis (Zhao et al., 2011). Depletion of Hippo (hpo), Wart (wts) and Salvador (sav) results in overgrowth of multiple tissues, and Yorkie (yki) is the key functional effector of the Hippo pathway in Drosophila (Harvey et al., 2003; Liu et al., 2016). The Hippo pathway is highly conserved in mammals (Dong et al., 2007). Yes‐associated protein (YAP) is the mammalian homologue of Yki. The Hippo/YAP pathway involvement in organ size control, tissue homeostasis, and cancer has been well documented but it also plays an essential role in the development of the cardiovascular system (Zhou et al., 2015) and maintaining vessel homeostasis. Specific knockout of YAP in vascular smooth muscle cells (VSMCs) in mice resulted in aberrant development of large arteries and perinatal lethality (Wang et al., 2014). Conditional inactivation of YAP in endothelial cells (ECs) in mice caused embryonic lethality by stopping the endothelial‐to‐mesenchymal transition in endocardial cushions, so YAP in ECs is indispensable for embryo development (Zhang et al., 2014). Also, YAP/transcriptional coactivator with PDZ‐binding motif (TAZ) signalling restricted by FOXC2 was found involved in a FOXC2‐mediated quiescent state and survival of lymphatic ECs under disturbed flow, which was essential to stabilize postnatal lymphatic vasculature (Sabine et al., 2015). Moreover, Hippo/YAP signalling was found to contribute to vascular remodelling and related CVDs, including pulmonary hypertension, atherosclerosis, aortic aneurysms, restenosis and angiogenesis. Here we discuss recent findings of the vital roles of Hippo/YAP signalling in CVDs.

Components of the Hippo/YAP pathway

Hippo signalling is an evolutionally conversed pathway from Drosophila to mammals and consists of a series of kinases and their downstream transcription factors (Dong et al., 2007). In mammals, the Hippo pathway mainly comprises mammalian STE20‐like protein kinase 1/2 (MST1/2), Salvador family WW domain‐containing protein 1, large tumour suppressor 1/2 (LATS1/2), MOB kinase activator 1A/B, mitogen‐activated protein 4 kinase 4, YAP/TAZ, and transcriptional enhancer associate domain family members 1–4 (TEAD1–4) (Chan et al., 2005; Callus et al., 2006; Hao et al., 2008; Lei et al., 2008; Zhao et al., 2008). When the Hippo pathway is activated, YAP/TAZ protein is phosphorylated by LATS1/2 on 5 serine residues, which results in its nuclear exclusion, ubiquitination and subsequent proteolytic degradation (Zhao et al., 2010) (Figure 1). In addition, YAP is phosphorylated by Src family tyrosine kinases at position Y357, which stabilizes YAP and increases the binding with p73 and Runt‐related transcription factor (Hong et al., 2005; Lapi et al., 2008). Besides TEAD1–4 and Runt‐related transcription factor, as transcription co‐activators, YAP/TAZ also interact with other transcriptional factors such as SMAD7, ErbB4, p73 and AP‐1 to control corresponding target gene expression (Ferrigno et al., 2002; Komuro et al., 2003; Zaidi et al., 2004; Zhao et al., 2008).

Figure 1.

Figure 1

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Components of the Hippo/YAP pathway. When the Hippo pathway is activated, YAP/TAZ is phosphorylated by LATS1/2 on serine residues, which leads to its cytoplasmic retention, degradation and nuclear exclusion. Inactivation of YAP/TAZ affects the activity of transcription factors that control proliferation, apoptosis, and differentiation.

Hippo/YAP pathway in vascular remodelling in CVDs

The proliferation, death and migration of cells and composition of ECM are essential cellular changes involved in vascular remodelling (Gibbons and Dzau, 1994; Chen et al., 2013). Inappropriate remodelling initiated by haemodynamics, oxidative stress or inflammation is accompanied by EC activation, VSMC migration and apoptosis, accelerated ECM degradation and destroyed vascular structure integrity. Although vascular remodelling diseases share some similar characteristics, in this review, we classify the roles of Hippo/YAP in vascular remodelling and the underlying mechanisms in five types of diseases, according to their main pathogenetic features.

Hippo/YAP pathway in pulmonary hypertension

Pulmonary hypertension, associated with right heart failure, is characterized by vasoconstriction and abnormal remodelling of pulmonary vessels, which leads to a progressive increase in pressure of the pulmonary artery (Harms et al., 2013). The ECM, containing molecules such as collagen, proteoglycans, laminin and fibronectin, provides structural integrity to various tissues as a physical scaffold (Hoon et al., 2016). Altered ECM stiffening and thickening in the vascular wall is caused by changing the deposition of various components of the ECM, a major process in vascular remodelling (Sasamura et al., 2006; Lemarie et al., 2010).

Variations in ECM stiffness are potent regulators of YAP/TAZ actvity. Dupont and colleagues monitored YAP/TAZ transcriptional activity in human mammary epithelial cells, MDA‐MB‐231 and HeLa cells grown on fibronectin‐coated acrylamide hydrogels with stiffness from 0.7 to 40 kPa. High ECM rigidity increased YAP/TAZ activity, as shown by the increased expression of TEAD target genes, connective tissue growth factor and ankyrin repeat domain 1; the induction of YAP/TAZ luciferase activity; and the subcellular localization of YAP/TAZ in nuclei (Dupont et al., 2011). In addition, YAP expression was higher in pulmonary arterial adventitial fibroblasts after culture in a stiff rather than soft matrix, but the total or phosphorylated forms of LATS1/2 or MST1/2 kinases were not changed (Bertero et al., 2015).

Several studies have focused on mechanisms of the ECM regulation of YAP/TAZ and suggested that cytoskeletal activity plays a key role in the process. Cell attachment to the ECM activated YAP by attenuating LATS1/2 activity, which was mediated by actin and microtubule cytoskeleton reorganization (Zhao et al., 2012). The nuclear cytoskeleton is also involved in YAP activation by mechano‐transduction, directly connected to cytosolic F‐actin by the Nesprin–SUN protein complexes (Bertrand et al., 2014; Driscoll et al., 2015). Various signal transduction mechanisms anticipate this process. For instance, YAP/TAZ activity regulated by ECM stiffness is attributed to the changed activity of Rho, one of the small GTPases, thereby linking physical environmental cues to cellular responses by regulating the cytoskeleton (Dupont et al., 2011; Hoon et al., 2016). Binding of integrins to ECM and mechanical stretching stimulate autophosphorylation of focal adhesion kinase on the Y397 residue, which increases YAP activity via the Src–PI3K–PDK1 pathway (Kim and Gumbiner, 2015). In addition, c‐Jun N‐terminal kinase signalling was identified as another possible mechanism (Codelia et al., 2014).

Intriguingly, activated YAP/TAZ can regulate the production of ECM as a positive feedback system controlling ECM stiffness. Depletion of YAP in cancer‐associated fibroblasts led to fewer thick collagen fibres and a lower elastic modulus, which in turn enhanced YAP activation (Calvo et al., 2013). Bertero and colleagues demonstrated the ECM stiffening‐activated YAP/TAZ induced microRNA130/301 (miR‐130/131) level by increasing the level of the transcription factor POU5F1/OCT4. The miR‐130/301 family activate the PPARγ–APOE–LRP8 axis, thereby inducing collagen deposition and LOX‐dependent remodelling. Hence, the mechano‐active feedback loop between ECM remodelling and YAP/TAZ could further promote activation of YAP/TAZ in a Hippo‐independent manner (Bertero et al., 2015).

The role of Hippo/YAP in pulmonary hypertension is still unclear. However, emerging evidence indicates the critical function of YAP in regulating proliferation and survival of pulmonary arterial VSMCs and pulmonary vascular remodelling through an ECM–YAP feedback loop in animal models. YAP/TAZ has been implicated in stiff matrix‐induced expression of glutaminase, which was attributed to pulmonary hypertension (Bertero et al., 2016). In addition, LATS1 was found inactivated in small remodelled pulmonary arteries and distal pulmonary arterial VSMCs in idiopathic pulmonary hypertension. The inactivation of LATS1 induced its reciprocal effector YAP, which increased the production and secretion of fibronectin and activated integrin‐linked kinase 1 (ILK1) in pulmonary arterial VSMCs. In turn, ILK1 negatively regulated LATS1, and this YAP–fibronectin–ILK1 signalling loop controls the proliferation and survival of pulmonary arterial VSMCs (Kudryashova et al., 2016). Therefore, a positive feedback loop involving actomyosin contractility, ECM stiffness and sustained YAP activation contributes to the process of pulmonary hypertension at different levels.

Hippo/YAP pathway in atherosclerosis

During the development of atherosclerosis, activation of ECs initiates an inflammatory process in the vessel wall. Monocytes in blood are attracted to the activated ECs, infiltrating into arterial walls and transforming to macrophages, which induces the local immune response and subsequent formation of atherosclerosis. Therefore, as a sensory and effector cell type involved in the onset of atherosclerosis, activated ECs play a prominent role in the initiation of atherosclerosis (Gibbons and Dzau, 1994; Gibbons, 1997), through the integration of various signals from the blood stream (Gibbons, 1997).

Among these signals, blood flow‐induced shear stress is a major determinant of the different distribution of atherosclerotic lesions in vessels. Because of the effect of flow pattern on vascular ECs, atherosclerosis more frequently develops at branches and curvatures in the arterial tree, where flow is disturbed, but less in the straight parts, where flow is steady and laminar (Sun et al., 2016). Such steady, laminar flow promotes the release of factors from ECs that inhibit coagulation, leukocyte diapedesis, and VSMC proliferation maintaining EC function and atheroprotection. In contrast, disturbed flow leads to endothelial dysfunction inducing a pro‐atherogenic environment (Chiu et al., 2009; Heo et al., 2014).

Recently, YAP linked to mechano‐transduction in cells was identified to be involved in EC activation and blood flow‐induced atherosclerosis in mouse models. Partial carotid ligation in ApoE −/− mice resulted in severe carotid atherosclerosis accompanied by activated YAP/TAZ (Wang et al., 2016b). In addition, endothelial‐specific YAP overexpression greatly exacerbated plaque formation in ApoE −/− mice (Wang et al., 2016b). In contrast, inhibition of YAP/TAZ translation by morpholino oligonucelotides decreased the expression of adhesion molecules, induced by partial carotid ligation, in the intima and the consequent leukocyte attachment. This treatment also reduced the overall size of atherosclerotic plaques and the disturbed flow‐induced carotid atherosclerosis (Wang et al., 2016a).

In vitro, atheroprone‐disturbed flow led to YAP/TAZ activation and its translocation into the nucleus (Wang et al., 2016a). Integrins, a family of transmembrane receptors mediating the physical attachment between cells and the ECM and transmitting signals, may be mechanosensors of shear stress (Sun et al., 2016). Our previous study found that unidirectional shear stress increased YAP phosphorylation by promoting integrin–Gα13 interaction and suppressing RhoA. As a result, reduced YAP activity inhibited c‐Jun N‐terminal kinase signalling and down‐regulated the expression of inflammatory factors such as cyclin A1 and CCL2 in a TEAD‐independent manner (Wang et al., 2016b). In contrast, laminar flow decreased YAP nuclear localization and activity in human ECs (Xu et al., 2016; Wang et al., 2016b), which indicated an atheroprone effect of YAP in response to different blood flow (Figure 2). These data, coupled with findings that the suppression of disturbed flow‐induced monocyte attachment to ECs by statin was attenuated by YAP/TAZ inhibition (Wang et al., 2016a), provide a rationale for considering YAP a potent therapeutic target in atherosclerosis.

Figure 2.

Figure 2

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Regulation of the Hippo pathway in endothelial cells. Shear stress regulates YAP phosphorylation by integrin /RhoA signalling in endothelial cells, which controls the expression of inflammatory factors and the development of atherosclerosis.

Hippo/YAP pathway and aortic aneurysms

Aortic aneurysms (AA) are a series of common conditions responsible for considerable cardiovascular morbidity and mortality, which present an enlarged aorta, more than 1.5 times the normal size (Aggarwal et al., 2011). AA mostly occur in the abdominal aorta but are also found in the thoracic aorta. Although AA shares similar pathogenetic characteristics with atherosclerosis, such as shear stress, inflammation and changed ECM deposition, VSMC apoptosis directly contributes to the destroyed structure in the aortic wall (Choke et al., 2005).

Stanford type A aortic dissection involves the ascending aorta. Maximum aortic wall velocity is decreased with such dissection in patients with elastic lamellae dissection and increased VSMC apoptosis (Isselbacher, 2005). The expression of YAP is decreased in the ascending aortic wall in patients with Stanford type A aortic dissection (Li et al., 2016). A similar phenomenon was observed in a mouse BAPN‐induced Stanford type A aortic dissection model (Jiang et al., 2016). YAP deficiency increased VSMC apoptosis under static conditions in vitro, and the change in mechanical stress induced YAP down‐regulation and VSMC apoptosis (Jiang et al., 2016).

Hippo/YAP pathway and restenosis

Restenosis is the recurrence of blood vessel stenosis, resulting in narrowed blood vessel and blocked blood flow. Clinically, restenosis always acts as a ‘silencer’ in atherosclerotic plaque‐removing surgery, which impedes satisfactory prognosis (Orford et al., 2000; Farooq et al., 2011). VSMCs regulate blood flow to target tissues by contracting and relaxing and thus exhibit an extraordinary phenotype plasticity during restenosis (Rzucidlo et al., 2007) and are considered an important target for restenosis treatment.

The Hippo/YAP pathway has been shown to participate in the signalling of a number of well‐established SMC‐phenotype switch‐related factors (Figure 3). For example, Xu et al. found that miR‐15b/16 promoted a VSMC contractile phenotype, at least in part, by targeting YAP (Xu et al., 2015). Also, the mechanism of the anti‐mitogenic effects of cAMP in VSMCs depends on Hippo/YAP signalling. Elevated cAMP‐induced actin remodelling suppressed the activity of both YAP and TAZ by increasing their nuclear export and inhibited TEAD‐dependent pro‐mitogenic gene expression (Kimura et al., 2016). The TxA2 (TP) receptor has been implicated in restenosis after vascular injury, inducing VSMC migration and proliferation (Savage et al., 1995; Feng et al., 2016). TP receptor‐specific agonists were found to induce VSMC migration and proliferation by activating YAP/TAZ, which was prevented by Rho inhibition or actin cytoskeleton disruption (Feng et al., 2016). Acting as a transcription coactivator, YAP inhibited the activity of the promoter of Hic‐5 and smooth muscle myosin heavy chain and induced expression of the TEAD target gene cyclin D1, a cell cycle‐regulating gene that controls cell proliferation (Wang et al., 2012). Additionally, YAP suppressed the expression of VSMC‐specific contractile genes by interacting with the myocardin–SRF complex (Xie et al., 2012).

Figure 3.

Figure 3

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Regulation of the Hippo pathway in smooth muscle cells. Several stimuli, such as mechanical stress, ECM stiffness and TP receptors regulate the Hippo pathway and the nuclear translocation of YAP/TAZ by modulating the activity of Rho GTPases or remodelling the actin cytoskeleton. The target genes of proliferation, phenotypic modulation, migration and apoptosis in smooth muscle cells are regulated by YAP/TAZ, which contribute to the development of aortic aneurysm and pulmonary hypertension.

Recent studies strongly suggest the involvement of Hippo/YAP signalling in the development of restenosis in rodent models. For instance, MST1, which can phosphorylate and suppress the activity of YAP/TAZ protein, was induced and activated in the balloon‐injured rat carotid artery (Ono et al., 2005). Overexpression of MST1 suppressed neointima formation 14 days after balloon injury (Ono et al., 2005). Of note, the expression of YAP was also greatly increased in a rat carotid artery balloon injury model as well as SMCs in growth medium. Elevated expression and activity of YAP mediated the switch of the SMC phenotype to the synthetic state and promoted neointima formation (Wang et al., 2012). YAP and MST1 levels were both simultaneously increased in SMCs in a neointima formation model, which indicates a complex mechanism, but these results demonstrated that activation of Hippo or inhibition of YAP would be a potential therapeutic approach to decreasing neointima formation.

Hippo/YAP pathway and angiogenesis

Angiogenesis is an important process to form new blood vessels under both physiological and pathophysiological conditions (Potente et al., 2011). During angiogenesis, some ECs select for tip cells, which in turn inhibits the tip‐cell fate of neighbouring cells. After that, the loosened cell–cell junctions by dissociating adhesion protein complexes such as VE‐cadherin and focal adhesion kinase facilitate ECs escaping from the original vessels, followed by EC proliferation and connecting with neighbouring vessels (Otrock et al., 2007; Potente et al., 2011). Angiogenesis is involved in ischaemia‐induced vascular remodelling, which restores perfusion in some ischaemic conditions, such as acute myocardial infarction and hind‐limb ischaemia (Carmeliet, 2003).

Hippo/YAP signalling is critical in regulating EC survival, proliferation and migration (Dupont et al., 2011). Phosphorylated YAP level is density‐dependently increased in ECs, caused by activation of VE–cadherin‐mediated cell junctional complex and PI3K/Akt signalling, and results in decreased YAP activity (Choi et al., 2015). Similarly, the actin‐binding protein EPS8 associates with VE‐cadherin organization to promote YAP nuclear translocation and transcriptional activity (Giampietro et al., 2015). As a result, YAP deficiency leads to defective tubular network formation of ECs on Matrigel and suppresses sprouting from EC‐coated beads in fibrin gel, which is mediated by attenuating the expression of angiopoietin‐2 (Choi et al., 2015). Alternatively, the Hippo pathway also controls angiogenesis independent of YAP/TAZ. Angiomotin is phosphorylated by LATS1/2, which disrupts its interaction with F‐actin and reduces focal adhesion, thereby resulting in reduced EC migration and angiogenesis in zebrafish embryos (Dai et al., 2013). These findings imply that YAP might be a potent therapeutic target to regulate angiogenesis for ischaemic diseases.

Conclusions and future perspectives

Haemostasis, the maintenance of the cardiovascular system, is crucial throughout the entire lifespan. Emerging evidence supports that the Hippo/YAP pathway plays an important role in vascular remodelling and thus in many CVDs. Hippo/YAP signalling is regulated in different stages of the physiological and pathological process of vascular remodelling. In turn, Hippo/YAP signalling can regulate ECM function and the SMC and EC phenotype, major processes during vascular remodelling and related CVDs including pulmonary hypertension, aortic aneurysms, atherosclerosis, restenosis and angiogenesis. However, other CVDs can be affected by the Hippo/YAP pathway, which need to be studied. As concluded by Yu et al. (2015), angiotensin II, a well established, endogenous vasopressor agent, can activate YAP/TAZ. Thus, the function of the Hippo/YAP pathway in hypertension is worthy of investigation. In addition, the regulation of YAP by HIF1α, AMPK, and mTOR may expand the known mechanisms of vascular remodelling regulated by the Hippo/YAP pathway. Moreover, the cardiovascular‐specific upstream signals and the crosstalk between the Hippo/YAP and other pathways remains to be investigated. Finally, the specific therapeutic target of the Hippo/YAP pathway in the cardiovascular system needs to be identified.

Nomenclature of targets and ligands

Key protein targets and the ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Southan et al., 2016), and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 (Alexander et al., 2015a,b,c,d).

Conflict of interest

The authors declare no conflicts of interest.

Acknowledgements

The present work is supported by the National Natural Science Foundation of China (81670388, 81370396, 81400320 and 81500445).

He, J. , Bao, Q. , Yan, M. , Liang, J. , Zhu, Y. , Wang, C. , and Ai, D. (2018) The role of Hippo/yes‐associated protein signalling in vascular remodelling associated with cardiovascular disease. British Journal of Pharmacology, 175: 1354–1361. doi: 10.1111/bph.13806.

Contributor Information

Chunjiong Wang, Email: wangchunjiong@126.com.

Ding Ai, Email: edin2000cn@gmail.com.

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