Matrix Remodeling Promotes Pulmonary Hypertension through Feedback Mechanoactivation of the YAP/TAZ-miR-130/301 Circuit

Thomas Bertero, Katherine A. Cottrill, Yu Lu, Christina M. Haeger, Paul Dieffenbach, Sofia Annis, Andrew Hale, Balkrishen Bhat, Vivek Kaimal, Ying Yi Zhang, Brian B. Graham, Rahul Kumar, Rajan Saggar, Rajeev Saggar, W. Dean Wallace, David J. Ross, Stephen M. Black, Sohrab Fratz, Jeffrey R. Fineman, Sara O. VargasKathleen J. Haley, Aaron B. Waxman, B. Nelson Chau, Laura E. Fredenburgh, Stephen Y. Chan

Research output: Contribution to journalArticle

81 Scopus citations

Abstract

Pulmonary hypertension (PH) is a deadly vascular disease with enigmatic molecular origins. We found that vascular extracellular matrix (ECM) remodeling and stiffening are early and pervasive processes that promote PH. In multiple pulmonary vascular cell types, such ECM stiffening induced the microRNA-130/301 family via activation of the co-transcription factors YAP and TAZ. MicroRNA-130/301 controlled a PPARγ-APOE-LRP8 axis, promoting collagen deposition and LOX-dependent remodeling and further upregulating YAP/TAZ via a mechanoactive feedback loop. In turn, ECM remodeling controlled pulmonary vascular cell crosstalk via such mechanotransduction, modulation of secreted vasoactive effectors, and regulation of associated microRNA pathways. In vivo, pharmacologic inhibition of microRNA-130/301, APOE, or LOX activity ameliorated ECM remodeling and PH. Thus, ECM remodeling, as controlled by the YAP/TAZ-miR-130/301 feedback circuit, is an early PH trigger and offers combinatorial therapeutic targets for this devastating disease.

Original languageEnglish (US)
Pages (from-to)1016-1032
Number of pages17
JournalCell Reports
Volume13
Issue number5
DOIs
StatePublished - Nov 3 2015

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Bertero, T., Cottrill, K. A., Lu, Y., Haeger, C. M., Dieffenbach, P., Annis, S., Hale, A., Bhat, B., Kaimal, V., Zhang, Y. Y., Graham, B. B., Kumar, R., Saggar, R., Saggar, R., Wallace, W. D., Ross, D. J., Black, S. M., Fratz, S., Fineman, J. R., ... Chan, S. Y. (2015). Matrix Remodeling Promotes Pulmonary Hypertension through Feedback Mechanoactivation of the YAP/TAZ-miR-130/301 Circuit. Cell Reports, 13(5), 1016-1032. https://doi.org/10.1016/j.celrep.2015.09.049