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

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Title
Distal vessel stiffening is an early and pivotal mechanobiological regulator of vascular remodeling and pulmonary hypertension
Author(s)
F Liu; C M Haeger; P B Dieffenbach; D Sicard; I Chrobak; A M F Coronata; M M S Velandia; S Vitali; R A Colas; P C Norris; A Marinkovic; X Liu; J Ma; C D Rose; Seon-Jin Lee; S A A Comhair; S C Erzurum; J D McDonald; C N Serhan; S R Walsh; D JTschumperlin; L E Fredenburgh
Bibliographic Citation
JCI Insight, vol. 1, no. 8, pp. e86987-e86987
Publication Year
2016
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.
ISSN
2379-3708
Publisher
Amer Soc Clinical Investigation Inc
DOI
http://dx.doi.org/10.1172/jci.insight.86987
Type
Article
Appears in Collections:
Division of Research on National Challenges > Environmental diseases research center > 1. Journal Articles
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