What is the clinical evidence from this study?

Study design: Other. Population: Pulmonary hypertension. Intervention: Treprostinil vs. Saline/Vehicle. Primary outcome: Pulmonary artery shear modulus (PAs < 100 μm).

June 1, 2016JCI Insight78 citationsOpen Access

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

Q: What are the key findings of this study?

Early intervention with the prostacyclin analog treprostinil prevented distal pulmonary artery stiffening and subsequent vascular and right ventricular sequelae in experimental pulmonary hypertension.

FLFei Liu CHChristina Mallarino Haeger PDPaul B. Dieffenbach

Key Result

Early intervention with the prostacyclin analog treprostinil prevented distal pulmonary artery stiffening and subsequent vascular and right ventricular sequelae in experimental pulmonary hypertension.

Structured PICO

Population

In vitro and in vivo experimental models of pulmonary hypertension, along with human lung tissue samples from patients with pulmonary arterial hypertension and controls.

Intervention

Prostacyclin analogs (iloprost in vitro; treprostinil 90 ng/kg/min i.v. in vivo) and manipulation of matrix stiffness.

Comparator

Vehicle/saline controls and soft matrix environments approximating normal pulmonary artery stiffness.

Outcome

Pulmonary artery stiffness (shear modulus measured via atomic force microscopy), cellular remodeling responses (proliferation, apoptosis, contraction, matrix deposition), COX-2 expression, and hemodynamic parameters (RVSP, RVH).surrogate

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.

Main Result

Absolute Event Rate: 2.1% vs 3.8%

Limitations

Atomic force microscopy (AFM) is invasive and requires unfixed tissue, modifying boundary conditions from their in situ state.
AFM measurements were made at room temperature in nonperfused tissue, not accounting for active cellular contributions, transmural distending pressure, or vascular flow.
Sampling challenges associated with the small spatial scale of measurements and inherent biological heterogeneity.
In human samples, lack of OCT inflation, heterogeneity of disease subtype and severity, and demographics may have affected measurements.
Treatment with prostanoids and other medications at the time of lung transplantation may have confounded stiffness assessment in human PAH tissue.
Atomic force microscopy (AFM) is an invasive technique with inherent limitations.

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 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.

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