Interaction between PGI2 and ET-1 pathways in vascular smooth muscle from Group-III pulmonary hypertension patients

Abstract

Pulmonary hypertension (PH) is characterized by an elevation of mean pulmonary artery pressure and it is classified into five groups. Among these groups, PH Group-III is defined as PH due to lung disease or hypoxia. Prostacyclin (PGI2) analogues (iloprost, treprostinil) and endothelin-1 (ET-1) receptor antagonists (ERA) (used alone or in combination) are therapies used for treating PH. The mechanisms underlying the positive/negative effects of combination treatment are not well documented, and in this study, we tested the hypothesis that the combination of a PGI2 analogue (iloprost, treprostinil) and an ERA may be more effective than either drug alone to treat vasculopathies observed in PH Group-III patients. Using Western blotting, ETA and ETB receptor expression were determined in human pulmonary artery (HPA) preparations derived from control and PH Group-III patients, and the physiologic impact of altered expression ratios was assessed by measuring ET-1 induced contraction of ex vivo HPA and human pulmonary veins (HPV) in an isolated organ bath system. In addition, the effects of single agent or combination treatments with a PGI2 analogue and an ERA on ET-1 release and HPA smooth muscle cells (hPASMCs) proliferation were determined by ELISA and MTT techniques, respectively. Our results indicate that the increased ETA/ETB receptor expression ratio in HPA derived from PH Group-III patients is primarily governed by a greatly depressed ETB receptor expression. However, contractions induced by ET-1 are not impacted in HPA and HPV derived from PH Group-III patients as compared to controls. Also, we found that the combination of an ETA receptor antagonist (BQ123) with iloprost provides greater inhibition of hPASMCs proliferation (-48±14% control;-32±06% PH) than either agent alone. Of note, while the ETB receptor antagonist (BQ788) increases ET-1 production from PH Group-III patients' preparations (HPA, parenchyma), even under these more proliferative conditions, iloprost and treprostinil are still effective to inhibit hPASMCs proliferation (-22/-24%). Our findings may provide new insights for the treatment of PH Group-III by combining a PGI2 analogue and a selective ETA receptor antagonist.

The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes

“…These vessels are covered by cells expressing high levels of α-smooth muscle actin (α-SMA) with ovoid cell bodies and multiple broad processes that almost completely ensheathe the underlying vessel (Grant et al, 2019;Figure 3A). Given that the identity of these cells is unresolved, and that they have been referred to as both pericytes (Peppiatt et al, 2006;Hall et al, 2014;Attwell et al, 2016;Grant et al, 2019) and SMCs (Hill et al, 2015;Grutzendler and Nedergaard, 2019), we refer to these cells here as "contractile mural cells" and to the segments of the vasculature Wroblewska et al, 1998;Harrison et al, 2008;Palazzo et al, Praticò and Dogné, 2005;Kaczynski et al, 2016;Longden et al, 2019;Upchurch and Leitinger, 2019;Ozen et al, Shima et al, 2007;Cortijo et al, 2012;Sugimura et al, 2012 Frizzled receptors…”

Microrna-342-3p Loaded by Human Umbilical Cord Mesenchymal Stem Cells-derived Exosomes Attenuates Deep Vein Thrombosis by Downregulating EDNRA

“…It has been implicated that increased EDNRA function is deleterious for cystic brosis airway [38]. Exactly, referral of selective EDNRA antagonist (BQ123) may be effectively adopted in pulmonary hypertension [39] and suppression of EDNRA greatly increases vessel sprouting, enhances angiogenesis and decreases pathological neovascularization in ischemic retinopathy [15].…”

MicroRNA-342-3p lOaded by Human Umbilical Cord Mesenchymal Stem Cells-derived Exosomes Attenuates Deep Vein Thrombosis by Downregulating EDNRA Running Title: Exosome Delivery of miR-342-3p in DVT

“…It has been implicated that increased EDNRA function is deleterious for cystic brosis airway [38]. Exactly, referral of selective EDNRA antagonist (BQ123) may be effectively adopted in pulmonary hypertension [39] and suppression of EDNRA greatly increases vessel sprouting, enhances angiogenesis and decreases pathological neovascularization in ischemic retinopathy [15].…”