Abstract 20479: Relaxin Inhibits TGFβ-induced Pulmonary Artery Smooth Muscle Cell Fibrogenic Differentiation Via Modulation Of SMAD-ERK Signaling
Introduction: Relaxin (RLN-2) exerts potent effects on smooth muscle tone and inhibits fibrosis. It is not known if RLN-2 contributes to regulatory mechanisms involved in maintenance of the pulmonary vascular cell homeostasis or pulmonary vascular remodeling.
Hypothesis: We tested whether or not RLN-2 and relaxin family peptide 1 receptor (RXFP1) signaling affects pulmonary arterial smooth muscle cell (PASMC) myogenic and fibrogenic differentiation.
Methods: Lung tissues from individuals with or without pulmonary arterial hypertension (PAH), and cultured microvascular endothelial cells and PASMC from these lungs were used for histologic and signaling studies.
Results: Immunohistochemistry revealed preferential expression of RXFP1 in vascular media but not intima of normal human pulmonary arteries and arterioles, and abundant expression in the hypertrophied media of pulmonary arteries from patients with idiopathic or heritable PAH. Expression of RXFP1 was detected by qRT-PCR in cultured primary PASMC from normal and IPAH lungs, but not pulmonary microvascular endothelial cells. Treatment of PASMC with RLN-2 (10-100 ng/mL) induced transient activation of ERK1/2 and markedly attenuated the release of intracellular calcium in response to Angiotensin II (100 nM). Pretreatment of PASMC with RLN-2 (10-100 ng/mL) dose-dependently inhibited transforming growth factor-β (TGFβ, 1 ng/mL)-mediated activation of SMAD3, and attenuated the TGFβ-induced expression of PAI-1, consistent with inhibition of canonical TGFβ signaling. Pretreatment with RLN-2 (10-100 ng/mL) abrogated the ability of TGF-β1 (1 ng/mL x 24 h) to induce a fibrogenic phenotype, based on the expression of fibronectin and type 1 collagen in PASMC.
Conclusions: Human PASMC express RXFP1. Stimulation of human PASMC with RLN2 activates ERK1/2, and inhibits canonical TGFβ-mediated signaling, transcriptional activity and phenotypic modulation. RLN-2/RXFP1 signaling may represent a therapeutic target for modulating pulmonary vascular tone and inhibiting pulmonary vascular remodeling associated with PAH.
Author Disclosures: L. Yung: None. I. Nikolic: None. J. Cavallo: Employment; Significant; Sanofi-Genzyme. D. Chain: Employment; Significant; Sanofi-Genzyme. S.C. Dwyer: Employment; Significant; Sanofi-Genzyme. M.R. Southwood: None. Z. Jia: Employment; Significant; Sanofi-Genzyme. I.O. Rosas: None. N.W. Morrell: None. S. Illiano: Employment; Significant; Sanofi. C. VanDeusen: Employment; Significant; Sanofi-Genzyme. P.B. Yu: Research Grant; Significant; Sanofi. Consultant/Advisory Board; Modest; Acceleron Pharma, Inc..
- © 2016 by American Heart Association, Inc.