title: Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension.
abstract: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bertero
authors.forename: William M
authors.initials: WM
authors.lastname: Oldham
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Cottrill
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pisano
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Vanderpool
authors.forename: Qiujun
authors.initials: Q
authors.lastname: Yu
authors.forename: Jingsi
authors.initials: J
authors.lastname: Zhao
authors.forename: Yiyin
authors.initials: Y
authors.lastname: Tai
authors.forename: Ying
authors.initials: Y
authors.lastname: Tang
authors.forename: Ying-Yi
authors.initials: YY
authors.lastname: Zhang
authors.forename: Sofiya
authors.initials: S
authors.lastname: Rehman
authors.forename: Masataka
authors.initials: M
authors.lastname: Sugahara
authors.forename: Zhi
authors.initials: Z
authors.lastname: Qi
authors.forename: John
authors.initials: J
authors.lastname: Gorcsan
authors.forename: Sara O
authors.initials: SO
authors.lastname: Vargas
authors.forename: Rajan
authors.initials: R
authors.lastname: Saggar
authors.forename: Rajeev
authors.initials: R
authors.lastname: Saggar
authors.forename: W Dean
authors.initials: WD
authors.lastname: Wallace
authors.forename: David J
authors.initials: DJ
authors.lastname: Ross
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Haley
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Waxman
authors.forename: Victoria N
authors.initials: VN
authors.lastname: Parikh
authors.forename: Teresa
authors.initials: T
authors.lastname: De Marco
authors.forename: Priscilla Y
authors.initials: PY
authors.lastname: Hsue
authors.forename: Alison
authors.initials: A
authors.lastname: Morris
authors.forename: Marc A
authors.initials: MA
authors.lastname: Simon
authors.forename: Karen A
authors.initials: KA
authors.lastname: Norris
authors.forename: Cedric
authors.initials: C
authors.lastname: Gaggioli
authors.forename: Joseph
authors.initials: J
authors.lastname: Loscalzo
authors.forename: Joshua
authors.initials: J
authors.lastname: Fessel
authors.forename: Stephen Y
authors.initials: SY
authors.lastname: Chan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002648:Child; D003094:Collagen / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D040542:Mechanotransduction, Cellular; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D059289:Vascular Stiffness; D055815:Young Adult
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; C000612286:WWTR1 protein, rat; D018698:Glutamic Acid; D003094:Collagen