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Mechanobiological Feedback Amplification of Vascular Remodeling in Pulmonary Arterial Hypertension is Modulated by COX-2-Derived Prostanoids

LE Fredenburgh

F Liu

X Liu

V Suárez

E Ifedigbo

A Marinkovic

DJ Tschumperlin

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Conference: 2012 International PHA Conference and Scientific Sessions

Release Date: 06.22.2012

Presentation Type: Abstracts

BACKGROUND: Recent studies suggest that increased pulmonary arterial stiffness contributes significantly to increased right ventricular afterload and is associated with increased mortality in pulmonary arterial hypertension (PAH) patients, however the role of PA stiffening in the pathogenesis of PAH has not yet been fully elucidated.

METHODS: Male Sprague-Dawley rats were treated with SU5416 (20 mg/kg) or vehicle subcutaneously and exposed to hypoxia (10% FiO2) for three weeks followed by re-exposure to normoxia for 2, 5, or 10 weeks (for a total of 5, 8, and 13 weeks). Lungs were harvested and pulmonary arterioles were mechanically characterized using atomic force microscopy (AFM) microindentation. Human PASMC were cultured on synthetic polyacrylamide substrates of defined stiffness spanning a shear modulus range of 0.1 to 25.6 kPa.

RESULTS: SU5416/hypoxia-exposed rats developed dramatic increases in right ventricular systolic pressure (58  2.5 vs. 22  1 mm Hg) and Fulton’s index (0.63  0.04 vs. 0.14  0.04) compared with controls, as well as marked pulmonary vascular remodeling. SU5416/hypoxia-exposed rats developed significant increases in stiffness in pulmonary arterioles <100 μm (1.26  0.8 kPa) compared with controls at 5 weeks, with progressive and sustained increases in PA stiffness at 8 and 13 weeks. Interestingly, pulmonary arterioles >100 μm demonstrated no increase in stiffness early following SU5416/hypoxia, however subsequently developed significant increases in shear modulus at 8 weeks (2.8  2.5 kPa) and 13 weeks (3.1  1.1 kPa) compared with controls. PASMC grown on substrates that span this stiffness range demonstrated exaggerated contractility and enhanced matrix deposition with increasing substrate stiffness, as well as increased proliferation, decreased apoptosis, and reduced cyclooxygenase-2 (COX-2)-derived prostanoid expression. Treatment with iloprost, a PGI2 analog, significantly attenuated stiffness-dependent increases in PASMC proliferation, matrix deposition, and contractility. Furthermore, increased matrix stiffness led to a significant reduction in COX-2 promoter activity in transiently transfected PASMC grown on substrates of pathologic stiffness.

CONCLUSIONS: Our results demonstrate that matrix remodeling in the pulmonary arterial wall fundamentally biases cellular behavior towards progressive vascular remodeling via previously unrecognized effects of matrix stiffening and suggest