Bone Marrow-Derived Endothelial Progenitor Cells Contribute to Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats via Inhibition of Store-Operated Ca2+ Channels.

Ran Miao,Zhenguo Zhai,Jason X.-J. Yuan,Wanmu Xie,Jun Wan,Jing Wang,Chen Wang,Jie Liu

doi:10.1155/2018/4892349

Abstract

Purpose This study aimed to explore whether bone marrow- (BM-) derived endothelial progenitor cells (EPCs) contributing to monocrotaline- (MCT-) induced pulmonary arterial hypertension (PAH) in rats via modulating store-operated Ca2+ channels (SOC). Methods Sprague Dawley (SD) rats were assigned into MCT group (n = 30) and control group (n = 20). Rats in MCT group were subcutaneously administered with 60 mg/kg MCT solution, and rats in control group were injected with equal amount of vehicle. After 3 weeks of treatment, right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI) of two groups were measured, and BM-derived EPCs were isolated. Immunochemistry identification and vasculogenesis detection of EPCs were then performed. [Ca2+]cyt measurement was performed to detect store-operated calcium entry (SOCE) in two groups, followed by determination of Orai and canonical transient receptor potential (TRPC) channels expression. Results After 3 weeks of treatment, there were significant increases in RVSP and RVHI in MCT group compared with control group, indicating that MCT successfully induced PAH in rats. Moreover, the SOCE ([Ca2+]cyt rise) in BM-derived EPCs of MCT group was lower than that of control group. Furthermore, the expression levels of Orai3, TRPC1, TRPC3, and TRPC6 in BM-derived EPCs were decreased in MCT group in comparison with control group. Conclusions The SOC activities were inhibited in BM-derived EPCs of MCT-treated rats. These results may be associated with the depressed expression of Orai3, TRPC1, TRPC3, and TRPC6, which are major mediators of SOC.

Highlights

Pulmonary arterial hypertension (PAH) is a fatal disorder characterized by an increase in pulmonary vascular resistance [1, 2]
Given the pathogenic role of Ca2+ signaling in PAH, the present study investigated whether BMderived endothelial progenitor cells (EPCs) contributed to PAH in the MCT rat model via modulating store-operated Ca2+ channels (SOC)
The results showed that rats in MCT group developed PAH after 3 weeks of MCT treatment as reflected by a remarkable increase in right ventricular systolic pressure (RVSP): 59.40 ± 8.13 mmHg in MCT rats versus 27.45 ± 0.89 mmHg in control rats (P< 0.05, Figure 1(a))

Summary

Introduction

Pulmonary arterial hypertension (PAH) is a fatal disorder characterized by an increase in pulmonary vascular resistance [1, 2]. It always leads to right ventricular (RV) failure and death [3, 4]. Despite advances in therapeutic options, this disease represents an incurable disease due to progressive clinical deterioration and an unacceptably high early mortality [5, 6]. Elucidation of key pathological mechanism underlying PAH development is still imperative. Accumulating evidences have confirmed that excessive pulmonary vascular remodeling is responsible for the elevated pulmonary vascular resistance in PAH [7,8,9]. In pulmonary arterial smooth muscle cells (PASMCs), the rise in cytosolic free Ca2+ concentration ([Ca2+]cyt) is identified as a key trigger for promoting the proliferation of PASMCs

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