Early intervention with the prostacyclin analog treprostinil prevented distal pulmonary artery stiffening and subsequent vascular and right ventricular sequelae in experimental pulmonary hypertension.
Distal pulmonary artery stiffening is an early mechanobiological event in pulmonary hypertension that suppresses COX-2, and this pathologic remodeling can be attenuated by prostacyclin analogs.
Absolute Event Rate: 2.1% vs 3.8%
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 I 2 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.
Liu et al. (2016) studied Pulmonary hypertension. Treprostinil vs. Saline/Vehicle was evaluated on Pulmonary artery shear modulus (PAs < 100 μm). Early intervention with the prostacyclin analog treprostinil prevented distal pulmonary artery stiffening and subsequent vascular and right ventricular sequelae in experimental pulmonary hypertension.