A Novel Protective Role for Matrix Metalloproteinase-8 in the Pulmonary Vasculature

Paul B. Dieffenbach, Christina Mallarino Haeger, Rakhshinda Rehman, Alexis M. Corcoran, Anna Maria F. Coronata, Shamsudheen K. Vellarikkal, Izabela Chrobak, Aaron B. Waxman, Sally H. Vitali, Lynette M. Sholl, Robert F. Padera, David Lagares, Francesca Polverino, Caroline A. Owen, Laura E. Fredenburgh

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Rationale: Mechanical signaling through cell–matrix interactions plays a major role in progressive vascular remodeling in pulmonary arterial hypertension (PAH). MMP-8 (matrix metalloproteinase-8) is an interstitial collagenase involved in regulating inflammation and fibrosis of the lung and systemic vasculature, but its role in PAH pathogenesis remains unexplored. Objectives: To evaluate MMP-8 as a modulator of pathogenic mechanical signaling in PAH. Methods: MMP-8 levels were measured in plasma from patients with pulmonary hypertension (PH) and controls by ELISA. MMP-8 vascular expression was examined in lung tissue from patients with PAH and rodent models of PH. MMP-8–/ and MMP-8+/+ mice were exposed to normobaric hypoxia or normoxia for 4–8 weeks. PH severity was evaluated by right ventricular systolic pressure, echocardiography, pulmonary artery morphometry, and immunostaining. Proliferation, migration, matrix component expression, and mechanical signaling were assessed in MMP-8–/ and MMP-8+/+ pulmonary artery smooth muscle cells (PASMCs). Measurements and Main Results: MMP-8 expression was significantly increased in plasma and pulmonary arteries of patients with PH compared with controls and induced in the pulmonary vasculature in rodent PH models. Hypoxia-exposed MMP-8–/ mice had significant mortality, increased right ventricular systolic pressure, severe right ventricular dysfunction, and exaggerated vascular remodeling compared with MMP-8+/+ mice. MMP-8–/ PASMCs demonstrated exaggerated proliferation and migration mediated by altered matrix protein expression, elevated integrin-β3 levels, and induction of FAK (focal adhesion kinase) and downstream YAP (Yes-associated protein)/TAZ (transcriptional coactivator with PDZ-binding motif) activity. Conclusions: MMP-8 is a novel protective factor upregulated in the pulmonary vasculature during PAH pathogenesis. MMP-8 opposes pathologic mechanobiological feedback by altering matrix composition and disrupting integrin-β3/FAK and YAP/TAZ-dependent mechanical signaling in PASMCs.

Original languageEnglish (US)
Pages (from-to)1433-1451
Number of pages19
JournalAmerican journal of respiratory and critical care medicine
Volume204
Issue number12
DOIs
StatePublished - Dec 15 2021
Externally publishedYes

Keywords

  • Cellular mechanotransduction
  • Integrin-b3
  • Pulmonary arterial hypertension
  • Pulmonary artery smooth muscle cells
  • YAP/TAZ

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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