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

• Published in: Cell reports (Cambridge) Vol. 13; no. 5; pp. 1016 - 1032
• Main Authors: Bertero, Thomas, Cottrill, Katherine A., Lu, Yu, Haeger, Christina M., Dieffenbach, Paul, Annis, Sofia, Hale, Andrew, Bhat, Balkrishen, Kaimal, Vivek, Zhang, Ying-Yi, Graham, Brian B., Kumar, Rahul, Saggar, Rajan, Saggar, Rajeev, Wallace, W. Dean, Ross, David J., Black, Stephen M., Fratz, Sohrab, Fineman, Jeffrey R., Vargas, Sara O., Haley, Kathleen J., Waxman, Aaron B., Chau, B. Nelson, Fredenburgh, Laura E., Chan, Stephen Y.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.11.2015; Elsevier
• Subjects: Animals; Apolipoproteins E - metabolism; Extracellular Matrix - metabolism; Extracellular Matrix - pathology; Feedback, Physiological; Humans; Hydrogen-Ion Concentration; Hypertension, Pulmonary - metabolism; Hypertension, Pulmonary - pathology; LDL-Receptor Related Proteins - metabolism; Mechanotransduction, Cellular; Mice; Mice, Inbred C57BL; MicroRNAs - genetics; PPAR gamma - metabolism; Rats; Rats, Sprague-Dawley; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2015.09.049

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. [Display omitted] •Matrix remodeling induces YAP/TAZ-miR-130/301 early in pulmonary hypertension (PH)•YAP/TAZ-miR-130/301 promotes matrix remodeling via a mechanoactive feedback loop•Such matrix remodeling drives pulmonary vascular activation and cellular crosstalk•Pharmacologic modulation of this circuit ameliorates matrix remodeling and PH Bertero et al. establish vascular matrix remodeling as an early, pervasive driver of pulmonary hypertension (PH) controlled by mechanoactive feedback from YAP/TAZ-microRNA-130/301 in multiple cell types. Inhibition of this circuit ameliorated matrix remodeling and PH, thus introducing promising cooperative therapies to treat this disease.