The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension
Open accessAbstract
Dysregulation of vascular stiffness and cellular metabolism occurs early in pulmonary hypertension (PH). However, the mechanisms by which biophysical properties of the vascular extracellular matrix (ECM) relate to metabolic processes important in PH remain undefined. In this work, we examined cultured pulmonary vascular cells and various types of PH-diseased lung tissue and determined that ECM stiffening resulted in mechanoactivation of the transcriptional coactivators YAP and TAZ (WWTR1). YAP/TAZ activation modulated metabolic enzymes, including glutaminase (GLS1), to coordinate glutaminolysis and glycolysis. Glutaminolysis, an anaplerotic pathway, replenished aspartate for anabolic biosynthesis, which was critical for sustaining proliferation and migration within stiff ECM. In vitro, GLS1 inhibition blocked aspartate production and reprogrammed cellular proliferation pathways, while application of aspartate restored proliferation. In the monocrotaline rat model of PH, pharmacologic modulation of pulmonary vascular stiffness and YAP-dependent mechanotransduction altered glutaminolysis, pulmonary vascular proliferation, and manifestations of PH. Additionally, pharmacologic targeting of GLS1 in this model ameliorated disease progression. Notably, evaluation of simian immunodeficiency virus-infected nonhuman primates and HIV-infected subjects revealed a correlation between YAP/TAZ-GLS activation and PH. These results indicate that ECM stiffening sustains vascular cell growth and migration through YAP/TAZ-dependent glutaminolysis and anaplerosis, and thereby link mechanical stimuli to dysregulated vascular metabolism. Furthermore, this study identifies potential metabolic drug targets for therapeutic development in PH.
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Cites
Role of YAP/TAZ in mechanotransduction
Dupont, S., Morsut, L., Aragona, M., Enzo, E., Giulitti, S., Cordenonsi, M., Zanconato, F., Le Digabel, J., Forcato, M., Bicciato, S., et al. (2011) · Nature · doi:10.1038/nature10137 · Cited by 5,979
Aerobic glycolysis: Meeting the metabolic requirements of cell proliferation
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Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells
Sullivan, L. B., Gui, D. Y., Hosios, A. M., Bush, L. N., Freinkman, E., & Vander Heiden, M. G. (2015) · Cell · doi:10.1016/j.cell.2015.07.017 · Cited by 1,173
Targeting Mitochondrial Glutaminase Activity Inhibits Oncogenic Transformation
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AMPK modulates Hippo pathway activity to regulate energy homeostasis
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Aerobic glycolysis tunes YAP/TAZ transcriptional activity
Enzo, E., Santinon, G., Pocaterra, A., Aragona, M., Bresolin, S., Forcato, M., Grifoni, D., Pession, A., Zanconato, F., Guzzo, G., et al. (2015) · The EMBO Journal · doi:10.15252/embj.201490379 · Cited by 414
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“analyzed by targeted LC-MS/MS as previously described (52).”
MethodSelf-citationvan den Heuvel, A. P. J., Jing, J., Wooster, R. F., & Bachman, K. E. (2012) · Cancer Biology & Therapy · doi:10.4161/cbt.21348 · Cited by 209
Two-signal requirement for growth-promoting function of Yap in hepatocytes
Su, T., Bondar, T., Zhou, X., Zhang, C., He, H., & Medzhitov, R. (2015) · eLife · doi:10.7554/elife.02948 · Cited by 64
Cited by
Mechanobiology of YAP and TAZ in physiology and disease
Panciera, T., Azzolin, L., Cordenonsi, M., & Piccolo, S. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.87 · Cited by 1,461
The Hippo Pathway: Biology and Pathophysiology
Ma, S., Meng, Z., Chen, R., & Guan, K.-L. (2019) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-013118-111829 · Cited by 1,387
The Hippo Signaling Pathway in Development and Disease
Zheng, Y., & Pan, D. (2019) · Developmental Cell · doi:10.1016/j.devcel.2019.06.003 · Cited by 867
Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy
Bertero, T., Oldham, W. M., Grasset, E. M., Bourget, I., Boulter, E., Pisano, S., Hofman, P., Bellvert, F., Meneguzzi, G., Bulavin, D. V., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2018.09.012 · Cited by 393
Self-citationDu, K., Hyun, J., Premont, R. T., Choi, S. S., Michelotti, G. A., Swiderska-Syn, M., Dalton, G. D., Thelen, E., Rizi, B. S., Jung, Y., et al. (2018) · Gastroenterology · doi:10.1053/j.gastro.2017.12.022 · Cited by 339
Metadata
- Authors
- Bertero, T., Oldham, W. M., Cottrill, K. A., Pisano, S., Vanderpool, R. R., Yu, Q., Zhao, J., Tai, Y., Tang, Y., Zhang, Y.-Y., Rehman, S., Sugahara, M., Qi, Z., Gorcsan, J., Vargas, S. O., Saggar, R., Saggar, R., Wallace, W. D., Ross, D. J., Haley, K. J., Waxman, A. B., Parikh, V. N., De Marco, T., Hsue, P. Y., Morris, A., Simon, M. A., Norris, K. A., Gaggioli, C., Loscalzo, J., Fessel, J., & Chan, S. Y.
- Venue
- Journal of Clinical Investigation
- Published
- 2016-08-22
- Volume
- 126
- Issue
- 9
- Pages
- 3313-3335
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- OpenAlex
- W2510865896
- Cited by
- 439
- References
- 9
- FWCI
- 27.01
- Type
- journal article
- Language
- en
- Open access
- bronze
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- The paper
- Bertero, T., Oldham, W. M., Cottrill, K. A., Pisano, S., Vanderpool, R. R., Yu, Q., Zhao, J., Tai, Y., Tang, Y., Zhang, Y.-Y., Rehman, S., Sugahara, M., Qi, Z., Gorcsan, J., Vargas, S. O., Saggar, R., Saggar, R., Wallace, W. D., Ross, D. J., . . . Chan, S. Y. (2016). Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension. Journal of Clinical Investigation. https://doi.org/10.1172/jci86387
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
