title: Distal vessel stiffening is an early and pivotal mechanobiological regulator of vascular remodeling and pulmonary hypertension.
abstract: Pulmonary arterial (PA) stiffness is associated with increased mortality in patients with pulmonary hypertension (PH); however, the role of PA stiffening in the pathogenesis of PH remains elusive. Here, we show that distal vascular matrix stiffening is an early mechanobiological regulator of experimental PH. We identify cyclooxygenase-2 (COX-2) suppression and corresponding reduction in prostaglandin production as pivotal regulators of stiffness-dependent vascular cell activation. Atomic force microscopy microindentation demonstrated early PA stiffening in experimental PH and human lung tissue. Pulmonary artery smooth muscle cells (PASMC) grown on substrates with the stiffness of remodeled PAs showed increased proliferation, decreased apoptosis, exaggerated contraction, enhanced matrix deposition, and reduced COX-2-derived prostanoid production compared with cells grown on substrates approximating normal PA stiffness. Treatment with a prostaglandin I2analog abrogated monocrotaline-induced PA stiffening and attenuated stiffness-dependent increases in proliferation, matrix deposition, and contraction in PASMC. Our results suggest a pivotal role for early PA stiffening in PH and demonstrate the therapeutic potential of interrupting mechanobiological feedback amplification of vascular remodeling in experimental PH.
authors.affiliation: Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Christina Mallarino
authors.initials: CM
authors.lastname: Haeger
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Dieffenbach
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Delphine
authors.initials: D
authors.lastname: Sicard
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.
authors.forename: Izabela
authors.initials: I
authors.lastname: Chrobak
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Anna Maria F
authors.initials: AM
authors.lastname: Coronata
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Margarita M
authors.initials: MM
authors.lastname: Suárez Velandia
authors.affiliation: Department of Anesthesia, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Sally
authors.initials: S
authors.lastname: Vitali
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Romain A
authors.initials: RA
authors.lastname: Colas
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Norris
authors.affiliation: Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Marinković
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Liu
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Anesthesia, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Chase D
authors.initials: CD
authors.lastname: Rose
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
authors.forename: Seon-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Suzy A A
authors.initials: SA
authors.lastname: Comhair
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Serpil C
authors.initials: SC
authors.lastname: Erzurum
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA.
authors.forename: Jacob D
authors.initials: JD
authors.lastname: McDonald
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
authors.affiliation: Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Walsh
authors.affiliation: Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Tschumperlin
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Fredenburgh