Flow-dependent YAP/TAZ activities regulate endothelial phenotypes and atherosclerosis

Wang, Kuei Chun; Yeh, Yi Ting; Nguyen, Phu Hung; Limqueco, Elaine; Lopez, Jocelyn; Thorossian, Satenick; Guan, Kun Liang; Li, Yi Shuan J.; Chien, Shu

doi:10.1073/pnas.1613121113

Cited by 336 publications

(373 citation statements)

References 31 publications

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“…YAP is a mechanical sensor whose cellular localization changes in response to various environmental stimuli including cell-cell interaction and alterations of cytoskeletal dynamics (34,35). We assessed whether YAP cellular localization affected CDC42 activity.…”

Section: Loss Of Cdc42 Caused Abnormal Vessel Morphology and Migrationmentioning

confidence: 99%

YAP/TAZ-CDC42 signaling regulates vascular tip cell migration

Sakabe

Fan

Odaka

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

158

157

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Angiogenesis and vascular remodeling are essential for the establishment of vascular networks during organogenesis. Here we show that the Hippo signaling pathway effectors YAP and TAZ are required, in a gene dosage-dependent manner, for the proliferation and migration of vascular endothelial cells (ECs) during retinal angiogenesis. Intriguingly, nuclear translocation of YAP and TAZ induced by Lats1/2-deletion blocked endothelial migration and phenocopied Yap/Taz-deficient mutants. Furthermore, overexpression of a cytoplasmic form of YAP (YAPS127D) partially rescued the migration defects caused by loss of YAP and TAZ function. Finally, we found that cytoplasmic YAP positively regulated the activity of the small GTPase CDC42, deletion of which caused severe defects in endothelial migration. These findings uncover a previously unrecognized role of cytoplasmic YAP/TAZ in promoting cell migration by activating CDC42 and provide insight into how Hippo signaling in ECs regulates angiogenesis.A ngiogenesis is a process of growth and remodeling in vascular networks that is essential for normal development. In adulthood, angiogenesis is activated as a reparative process, for example, during wound healing (1, 2). Aberrantly regulated angiogenesis can also be a component of disease (3) and can play a key role in tumor growth and metastasis (4), inflammatory diseases (5), diabetic retinopathy, and retinopathy of prematurity (6).Retinal angiogenesis in mice begins at postnatal day 0 (P0). The retinal vasculature initiates its expansion from the optic nerve head and migrates outwards along a preexisting network of astrocytes (7,8). This results in the formation of the superficial vascular plexus within the retinal ganglion cell layer during the first 8 d (9, 10). Endothelial cells (ECs) then migrate along nerve fibers to establish deep and intermediate vascular layers (9,11). Cell proliferation and migration are essential for angiogenesis and these cell responses are regulated by many different signaling pathways, including the VEGF, Notch, Wnt, FGF, BMP, and integrin signaling responses (9, 12-16). VEGFA and CDC42 are known to regulate extension of the angiogenic front and filopodia formation in angiogenic tip cells (2,17,18).The Hippo signaling pathway is an evolutionarily conserved, pivotal regulator of cell proliferation and organogenesis. YAP and TAZ are key components of the Hippo signaling pathway and function as transcription cofactors that regulate downstream gene expression via association with DNA binding proteins such as 20). Loss of Hippo signaling can drive the expression of genes that regulate cell proliferation and survival (diap1, bantam, cyclin E, and E2F1), the Hippo pathway (Kibra, Crb, and Fj), and cell-cell interaction (E-Cadherin, Serrate, Wingless, and Vein) (20). The activity of YAP and TAZ is regulated by the LATS1 and LATS2 kinases. These kinases phosphorylate YAP and TAZ, thus preventing their nuclear translocation and regulating transcriptional activity. Although the function of YAP and TAZ in the ...

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Section: Loss Of Cdc42 Caused Abnormal Vessel Morphology and Migrationmentioning

confidence: 99%

YAP/TAZ-CDC42 signaling regulates vascular tip cell migration

Sakabe

Fan

Odaka

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

158

157

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“…As an oncoprotein, YAP activation is found in several human cancers 41–44 , and it plays a key role in the Hippo pathway to control cell proliferation in response to cell contact 41 . Finally, YAP activation promotes endothelial cell proliferation and inflammatory response in atherosclerosis 45 . Therefore, it is logical to predict that the Hippo signaling pathway could be the central pathway regulating each member of the pathogenic triumvirate in ARPKD/CHF.…”

Section: Discussionmentioning

confidence: 99%

Increased YAP Activation Is Associated With Hepatic Cyst Epithelial Cell Proliferation in ARPKD/CHF

et al. 2017

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Autosomal recessive polycystic kidney disease/congenital hepatic fibrosis (ARPKD/CHF) is a rare but fatal genetic disease characterized by progressive cyst development in the kidneys and liver. Liver cysts arise from aberrantly proliferative cholangiocytes accompanied by pericystic fibrosis and inflammation. Yes associated protein (YAP), the downstream effector of the Hippo signaling pathway, is implicated in human hepatic malignancies such as hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma, but its role in hepatic cystogenesis in CHF/ARPKD is unknown. We studied the role of the YAP in hepatic cyst development using polycystic kidney (PCK) rats, an orthologous model of ARPKD, and in human ARPKD/CHF patients. The liver cyst wall epithelial cells (CWECs) in PCK rats were highly proliferative and exhibited expression of YAP. There was increased expression of YAP target genes, Cyclin D1 and Ctgf (connective tissue growth factor), in PCK rat livers. Extensive expression of YAP and its target genes was also detected in human ARPKD/CHF liver samples. Finally, pharmacological inhibition of YAP activity with verteporfin and short-hairpin (sh) RNA-mediated knockdown of YAP expression in isolated liver CWECs significantly reduced their proliferation. These data indicate that increased YAP activity, possibly through dysregulation of the Hippo signaling pathway, is associated with hepatic cyst growth in ARPKD/CHF.

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“…Recent work has shown that YAP/TAZ is regulated by stiffness, cell shape, and mechanical forces, and its dysregulation is associated with diseases including atherosclerosis, fibrosis, and cancer . In myeloid cells, YAP/TAZ has been found to be involved in monocyte adhesion to inflamed endothelium, TGFβ1‐induced fibrotic M2 polarization, and tumor‐associated M2 polarization, but a definitive role for YAP in macrophage mechanotransduction remains elusive. The myocardin‐related transcription factor A (MRTF‐A) is another transcriptional regulator that has been observed to be influenced by mechanical cues .…”

Section: Molecular Mechanisms Of Mechanotransductionmentioning

confidence: 99%

Biophysical regulation of macrophages in health and disease

Meli

Veerasubramanian

Atcha

et al. 2019

Journal of Leukocyte Biology

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Macrophages perform critical functions for homeostasis and immune defense in tissues throughout the body. These innate immune cells are capable of recognizing and clearing dead cells and pathogens, and orchestrating inflammatory and healing processes that occur in response to injury. In addition, macrophages are involved in the progression of many inflammatory diseases including cardiovascular disease, fibrosis, and cancer. Although it has long been known that macrophages respond dynamically to biochemical signals in their microenvironment, the role of biophysical cues has only recently emerged. Furthermore, many diseases that involve macrophages are also characterized by changes to the tissue biophysical environment. This review will discuss current knowledge about the effects of biophysical cues including matrix stiffness, material topography, and applied mechanical forces, on macrophage behavior. We will also describe the role of molecules that are known to be important for mechanotransduction, including adhesion molecules, ion channels, as well as nuclear mediators such as transcription factors, scaffolding proteins, and epigenetic regulators. Together, this review will illustrate a developing role of biophysical cues in macrophage biology, and also speculate upon molecular targets that may potentially be exploited therapeutically to treat disease.

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Flow-dependent YAP/TAZ activities regulate endothelial phenotypes and atherosclerosis

Cited by 336 publications

References 31 publications

YAP/TAZ-CDC42 signaling regulates vascular tip cell migration

YAP/TAZ-CDC42 signaling regulates vascular tip cell migration

Increased YAP Activation Is Associated With Hepatic Cyst Epithelial Cell Proliferation in ARPKD/CHF

Biophysical regulation of macrophages in health and disease

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