Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension

• Published in: The Journal of clinical investigation Vol. 126; no. 9; pp. 3313 - 3335
• Main Authors: Bertero, Thomas, Oldham, William M., Cottrill, Katherine A., Pisano, Sabrina, Vanderpool, Rebecca R., Yu, Qiujun, Zhao, Jingsi, Tai, Yiyin, Tang, Ying, Zhang, Ying-Yi, Rehman, Sofiya, Sugahara, Masataka, Qi, Zhi, Gorcsan, John, Vargas, Sara O., Saggar, Rajan, Saggar, Rajeev, Wallace, W. Dean, Ross, David J., Haley, Kathleen J., Waxman, Aaron B., Parikh, Victoria N., De Marco, Teresa, Hsue, Priscilla Y., Morris, Alison, Simon, Marc A., Norris, Karen A., Gaggioli, Cedric, Loscalzo, Joseph, Fessel, Joshua, Chan, Stephen Y.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.09.2016
• Subjects: Acidification; Adolescent; Adult; Aged; Amino acids; Animals; Biomedical research; Cardiology and cardiovascular system; Cell proliferation; Child; Collagen - metabolism; Colleges & universities; Development and progression; Disease; Endothelial Cells - metabolism; Experiments; Extracellular Matrix - metabolism; Female; Gene expression; Glutamic Acid - metabolism; Glycolysis; Grants; Health aspects; Human health and pathology; Humans; Hypertension, Pulmonary - metabolism; Infant; Intracellular Signaling Peptides and Proteins - metabolism; Lentivirus; Life Sciences; Male; Mechanotransduction, Cellular; Medicine; Metabolism; Metabolites; Middle Aged; Myocytes, Smooth Muscle - metabolism; Phosphoproteins - metabolism; Phosphorylation; Pulmonary hypertension; Rats; Rats, Sprague-Dawley; Retroviridae; Smooth muscle; Vascular Stiffness; Young Adult
• DOI: 10.1172/JCI86387
• ISSN: 0021-9738

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.