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Distal vessel stiffening is an early and pivotal mechanobiological regulator of vascular remodeling and pulmonary hypertension
Fei Liu, … , Daniel J. Tschumperlin, Laura E. Fredenburgh
Fei Liu, … , Daniel J. Tschumperlin, Laura E. Fredenburgh
Published June 2, 2016
Citation Information: JCI Insight. 2016;1(8):e86987. https://doi.org/10.1172/jci.insight.86987.
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Research Article Pulmonology Vascular biology

Distal vessel stiffening is an early and pivotal mechanobiological regulator of vascular remodeling and pulmonary hypertension

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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 I2 analog 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

Fei Liu, Christina Mallarino Haeger, Paul B. Dieffenbach, Delphine Sicard, Izabela Chrobak, Anna Maria F. Coronata, Margarita M. Suárez Velandia, Sally Vitali, Romain A. Colas, Paul C. Norris, Aleksandar Marinković, Xiaoli Liu, Jun Ma, Chase D. Rose, Seon-Jin Lee, Suzy A.A. Comhair, Serpil C. Erzurum, Jacob D. McDonald, Charles N. Serhan, Stephen R. Walsh, Daniel J. Tschumperlin, Laura E. Fredenburgh

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Figure 1

Increased PA stiffness in rat pulmonary hypertension models and human PAH.

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Increased PA stiffness in rat pulmonary hypertension models and human PA...
(A and C) Sprague-Dawley rats were treated with monocrotaline (MCT) or PBS (n = 6 per group) and lungs harvested after 4 weeks. (B and D) Sprague-Dawley rats were treated with SU5416 (S) or vehicle (V), exposed to hypoxia (H) or normoxia (N) for 3 weeks, and then returned to normoxia for an additional 5 weeks (n = 4 per group). Pulmonary arterioles (PA) < 100 μm (A and B) and lung parenchyma (C and D) were mechanically characterized via AFM microindentation. Horizontal lines represent the mean shear modulus of each group, and each symbol corresponds to 1 PA (A and B) or parenchymal region (C and D). Statistical significance was determined by a mixed model with treatment as a fixed effect and individual rats as a random effect. (E and F) AFM microindentation was used to mechanically characterize PAs (E) and lung parenchyma (F) in human lung samples from PAH (n = 17; IPAH n = 8, FPAH n = 3, APAH n = 6) and control subjects (n = 7). Horizontal lines represent the mean shear modulus of each group, and each symbol corresponds to 1 PA (E) or parenchymal region (F). Statistical significance was determined by a mixed model with disease state as a fixed effect and subgroups and individual patients as nested fixed effects.
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