Olfactory receptors in pulmonary arterial hypertension: A novel pathway of vascular remodeling?

Pulmonary arterial hypertension (PAH) is due to progressive obstruction of pulmonary arteries, thus leading to right heart failure and death. Breath volatile organic compounds (VOCs) can discriminate PAH and controls. Thus, a unique breath-print of PAH is detected using an artificial nose. VOCs target olfactory receptors (ORs) in olfaction. Interestingly, ORs are detected in peripheral tissues not related to olfaction and their deregulation is associated to cancer development. PSGR, encoded by the OR51E2 gene, is one of the ORs. Because vascular cells in PAH exhibit properties of cancer cells, we propose the ground-breaking hypothesis that ORs participate to vascular remodeling leading to PAH. Thus we aim to determine whether a deregulated expression and function of the pulmonary vascular PSGR could participate to the pathological phenotype of vascular cells, and its potential use as a novel therapeutic target in PAH. PSGR gene and protein expression were assessed in total lung, distal pulmonary arteries and PASMCs from PAH patients compared to controls using qRT-PCR and western blot. We evaluated proliferation (Ki67) and apoptosis (TMRM) after siRNA-directed silencing of PSGR expression in PASMCs. We demonstrate that PSGR expression is significantly increased (50%) in PASMC, in total lung and isolated pulmonary arteries from PAH patients compared to controls. PSGR silencing in PAH-PASMCs decreased both cell proliferation (20%) and resistance to apoptosis (25%). This deregulated OR expression in PAH PASMCs opens a new avenue in PAH pathophysiology. The whole spectrum of ORs is currently investigated using microarrays and deregulated ORs will be evaluated both in vitro and in vivo

PSGR olfactory receptor: A new potential target in pulmonary arterial hypertension

International audiencePulmonary arterial hypertension {PAH) is a rare progressive disease due to dista lvascular remodeling, leading to right heart failure and death. PSGR is an olfactory receptor {OR) that has been recently detected in peripheral tissues. Moreover, PSGR overexpression is associated with pro-proliferative phenotype in prostate cancer. Since PAH vascular cells are characterized by cancer-like over-proliferation, we hypothesized that PSGR might participate in the vascular remodeling leading to PAH. Here we aimed to determine whether upregulation of PSGR is implicated in PAH pathological phenotype, and to explore PSGR as a novel therapeutic target in PAH. PSGR gene and protein expressions were assessed in total lung, distal pulmonary arteries and Pulmonary Artery Smooth Muscle Cells {PASMC) and Endothelial Cells from PAH patients and controls using qRT-PCR and western blot. We evaluated proliferation and apoptosis using Ki67 and TMRM. siRNAdirected silencing of PSGR and STAT3, was used to inhibit the specific expression in PASMCs, whereas PP2 was used to inhibit Src activation. We demonstrate that PSGR expression is significantly increased in PASMCs and isolated pulmonary arteries of PAH patients. We also show a trend to decreased Src activation and restored BMPR2 expression as a function of PSGR inhibition in PAH-PASMC. Moreover, inhibition of STAT3 and/or Src partially decreased PSGR mRNA expression. PSGR silencing reversed the PAH pro-proliferative phenotype in human PASMC. To conclude, overexpression of PSGR leads to a pro-proliferative phenotype of PASMCs in PAH, which could be decreased by PSGR inhibition. Src-STAT3 pathway activation is potentially the bridge linking PSGR and the pathophysiology

Functional interaction between PDGFβ and GluN2B-containing NMDA receptors in smooth muscle cell proliferation and migration in pulmonary arterial hypertension

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NMDA-Type Glutamate Receptor Activation Promotes Vascular Remodeling and Pulmonary Arterial Hypertension

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