Chemerin Added to Endothelin-1 Promotes Rat Pulmonary Artery Smooth Muscle Cell Proliferation and Migration

Abstract

Background: While chemerin has been shown to increase proliferation and migration of systemic vascular smooth muscle cells (SMCs) contributing therefore to the development of hypertension, this remains to be clarified for the pulmonary circulation. Methods: Expression of chemerin and its three receptors (CMKRL1, CCRL2, GPR1) was examined by immunohistochemistry and RTq-PCR in lungs, pulmonary artery, and thoracic aorta from Wistar rats. Primary cultured rat pulmonary artery and thoracic aorta SMCs treated with recombinant chemerin (tested from 5.10 −9 to 10 −7 mol/L) were assessed for proliferation and migration (both with 10 −7 mol/L endothelin-1), as well as for staurosporine-induced apoptosis. Results: In pulmonary artery and thoracic aorta, CMKLR1 expression was detected in both endothelial cells and SMCs. In primary cultured pulmonary artery SMCs, chemerin and its three receptors were expressed, and CMKLR1 expression was higher than those of CCRL2 and GPR1. Chemerin added to endothelin-1 increased pulmonary artery SMC proliferation, while chemerin or endothelin-1 alone did not. This effect was less pronounced in thoracic aorta SMCs. Chemerin induced pulmonary artery and thoracic aorta SMC migration, which was exacerbated by endothelin-1 and more pronounced in thoracic aorta SMCs. Chemerin concentration-dependently reduced staurosporineinduced apoptosis in both pulmonary artery and thoracic aorta SMCs. In pulmonary artery SMCs, endothelin-1 treatment increased the expression of CMKLR1, CCRL2, and GPR1, while these expressions were not altered in thoracic aorta SMCs. Conclusion: Chemerin/CMKRL1 signaling, in conjunction with a key mediator in the pathogenesis of pulmonary hypertensive diseases, endothelin-1, stimulated proliferation and migration, and increased resistance to apoptosis in rat primary cultured pulmonary artery SMCs. Our results suggest that this signaling could play a role in pulmonary artery remodeling observed in pulmonary hypertension.

Biomarkers of haemodynamic severity of systemic sclerosis-associated pulmonary arterial hypertension by serum proteome analysis

“…Because the binding of chemerin to its receptor CMKLR1 stimulates the proliferation and migration of PA-SMCs,26 we first performed a single cell RNA-sequencing (scRNAseq) analysis in lungs from four SSc-PAH and four non-SSc controls to obtain a global view of chemerin and CMKLR1 expression patterns. Our scRNAseq data indicate that CMKLR1 was predominantly expressed by a subpopulation of cells expressing α-SMA and clustering with PA-SMCs/pericytes and myofibroblasts; as well as by endothelial cells and macrophages (figure 4).…”

Resolvin E1 Attenuates Pulmonary Hypertension by Suppressing Wnt7a/β-Catenin Signaling

“…47 On the contrary, others reported that chemerin/ChemR23 signaling stimulated proliferation in human VSMCs, 48 and in conjunction with endothelin-1, also promoted proliferation and migration in rat PASMCs. 17 These discrepancies might be due to the different receptor conformations of chemR23 bond by chemerin peptides and RvE1, which resulted in various levels of activation of different downstream signaling molecules. 49 Both canonical and noncanonical Wnt/β-catenin pathways are involved in the pathogenesis of PAH, including heritable and idiopathic PAH.…”

“…6,16 Notably, ChemR23 is also highly expressed in vascular smooth muscle cells (VSMCs) and plays important role in maintaining VSMC functions such as proliferation and contraction. 17,18 RvE1 confers vascular protection against atherosclerosis, 19 aortic valve stenosis, 20 and vascular calcification 21 through ChemR23. However, the role of the RvE1/ChemR23 axis in hypoxia-induced pulmonary vascular remodeling remains unclear.…”

Role of Chemerin in Cardiovascular Diseases

“…The proliferation and migration of VSMCs are involved in vascular remodelling, and the abnormal vascular structure is accompanied by vascular dysfunction [ 129 ]. Studies show that short-term in vitro treatment of VSMCs with chemerin (20 min) increased the proliferation and migration capacity of VSMCs via MAPK and Akt/ERK signalling [ 130 , 131 ], the endothelin-1 dependent pathway [ 132 ], and increased autophagy [ 133 ]. Interestingly, prolonged incubation of VSMCs with chemerin (6 h) led to VSMC’s apoptosis [ 126 ], suggesting that chemerin may exert different functions at different stages of vascular remodelling and dysfunction [ 120 ].…”