The physiologic process of postnatal ductus arteriosus (DA) closure consists of vasoconstriction followed by vascular remodeling. We have recently reported that B-type natriuretic peptide (BNP), a potent vasodilator, also has anti-remodeling effects in pulmonary vasculature. However, its effects on DA have not been elucidated. We investigated whether BNP can prevent DA closure, and if so, the underlying mechanisms. Using in vivo studies, we examined effects of BNP (10 mg/kg, ip at birth) on DA closure in neonatal rats within 4 h after birth. We found that in control rats, the DA spontaneously closed at 4 h with a decreased DA diameter, enhanced intimal thickening, and luminal occlusion. BNP prevented DA closure at 4 h with a preserved DA diameter, attenuated intimal thickening, and preserved luminal patency. Ex vivo, BNP attenuated oxygen-induced vasoconstriction of isolated DA rings of newborn rats. These vasodilating effects were blunted by Rp-8-Br-PET-cGMPS, a cGMP inhibitor. In vitro, BNP inhibited angiotensin II (Ang II)-induced proliferation and migration of DA smooth muscle cells (DASMCs). BNP inhibited Ang II-induced mitochondrial reactive oxygen species (ROS) production and calcium overload in DASMCs. Finally, BNP inhibited Ang II-induced ERK1/2 activation. These in vitro effects were antagonized by Rp-8-Br-PET-cGMPS. In conclusion, BNP prevents postnatal DA closure by both vasodilation and anti-remodeling through the cGMP pathway. The mechanisms underlying anti-remodeling effects include anti-poliferation and anti-migration, with attenuation of mitochondrial ROS production and intracellular calcium and ERK1/2 signaling. Therefore, the BNP/cGMP pathway can be a promising therapeutic target for clinical management of DA patency.
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September 2018
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A scanning electron micrograph (digitally altered and colourized, 4000× magnification) depicting a mesenchymal stem cell (orange) encapsulated in a self-assembling peptide hydrogel. In volume 132, issue 17 of Clinical Science, McFetridge et al. discuss the use of hydrogel materials to unlock the potential of stem cell therapy to treat chronic kidney disease. This image was provided by the authors and produced in collaboration with Dr Simon Crawford at the Ramaciotti Centre for Cryo-Electron Microscopy, and the Monash Teaching Resource Support Unit.Close Modal
Research Article|
September 19 2018
B-type natriuretic peptide prevents postnatal closure of ductus arteriosus by both vasodilation and anti-remodeling in neonatal rats
Jwu-Lai Yeh;
Jwu-Lai Yeh
*
1Department of Pharmacology and Graduate Institute of Medicine, College of Medicine, Kaohsiung, Taiwan
2Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
3Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung, Taiwan
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Jiunn-Ren Wu;
Jiunn-Ren Wu
*
4Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
5Department of Pediatrics, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
6Department of Pediatrics, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
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Bin-Nan Wu;
Bin-Nan Wu
1Department of Pharmacology and Graduate Institute of Medicine, College of Medicine, Kaohsiung, Taiwan
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Sheau-Fang Yang;
Sheau-Fang Yang
7Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
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Zen-Kong Dai;
Zen-Kong Dai
4Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
5Department of Pediatrics, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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Shu-Fen Liou;
Shu-Fen Liou
8Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan
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Jong-Hau Hsu
4Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
5Department of Pediatrics, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
Correspondence: Jong-Hau Hsu (jhh936@yahoo.com.tw)
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Clin Sci (Lond) (2018) 132 (18): 2045–2058.
Article history
Received:
March 16 2018
Revision Received:
August 14 2018
Accepted:
August 16 2018
Accepted Manuscript online:
August 17 2018
Citation
Jwu-Lai Yeh, Jiunn-Ren Wu, Bin-Nan Wu, Sheau-Fang Yang, Zen-Kong Dai, Shu-Fen Liou, Jong-Hau Hsu; B-type natriuretic peptide prevents postnatal closure of ductus arteriosus by both vasodilation and anti-remodeling in neonatal rats. Clin Sci (Lond) 28 September 2018; 132 (18): 2045–2058. doi: https://doi.org/10.1042/CS20180201
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