Role of extracellular matrix in the pathogenesis of pulmonary arterial hypertension

Thenappan Thenappan, Stephen Y. Chan, E. Kenneth Weir

Research output: Contribution to journalReview articlepeer-review

66 Scopus citations


Pulmonary arterial hypertension (PAH) is characterized by remodeling of the extracellular matrix (ECM) of the pulmonary arteries with increased collagen deposition, cross-linkage of collagen, and breakdown of elastic laminae. Extracellular matrix remodeling occurs due to an imbalance in the proteolytic enzymes, such as matrix metalloproteinases, elastases, and lysyl oxidases, and tissue inhibitor of matrix metalloproteinases, which, in turn, results from endothelial cell dysfunction, endothelial-to-mesenchymal transition, and inflammation. ECM remodeling and pulmonary vascular stiffness occur early in the disease process, before the onset of the increase in the intimal and medial thickness and pulmonary artery pressure, suggesting that the ECM is a cause rather than a consequence of distal pulmonary vascular remodeling. ECM remodeling and increased pulmonary arterial stiffness promote proliferation of pulmonary vascular cells (endothelial cells, smooth muscle cells, and adventitial fibroblasts) through mechanoactivation of various signaling pathways, including transcriptional cofactors YAP/TAZ, transforming growth factor-β, transient receptor potential channels, Toll-like receptor, and NF-κB. Inhibition of ECM remodeling and mechanotransduction prevents and reverses experimental pulmonary hypertension. These data support a central role for ECM remodeling in the pathogenesis of the PAH, making it an attractive novel therapeutic target.

Original languageEnglish (US)
Pages (from-to)H1322-H1331
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number5
StatePublished - Oct 29 2018

Bibliographical note

Funding Information:
This work was supported by American Heart Association Scientific Development Grant 15SDG25560048 (to T. Thenappan), National Institutes of Health Grants R01-HL-124021, HL-122596, HL-138437, and UH2-TR-002073, and an American Heart Association Established Investigator award (to S. Y. Chan).

Publisher Copyright:
© 2018 the American Physiological Society.


  • Collagen
  • Compliance
  • Mechanotransduction
  • Right ventricle
  • Stiffness


Dive into the research topics of 'Role of extracellular matrix in the pathogenesis of pulmonary arterial hypertension'. Together they form a unique fingerprint.

Cite this