B-type natriuretic peptide prevents postnatal closure of ductus arteriosus by both vasodilation and anti-remodeling in neonatal rats

Abstract

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 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., 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. , 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 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.

Cinaciguat Prevents Postnatal Closure of Ductus Arteriosus by Vasodilation and Anti-remodeling in Neonatal Rats

“…We used Orcein stain to reveal the internal elastic lamina, the boundary line between the intima and media layers of the DA, for further determining intimal thickening and medial area of the DA. The intimal thickening and luminal area were estimated by (intimal area)/(medial area) and (luminal area)/(total vessel area), respectively, as previously described ( Yeh et al, 2018 ). The average of at least three sections was used as the value for each tissue.…”

“…All the DA rings were initially stabilized for at least 60 min with a modified Krebs–Henseleit solution, which was equilibrated under hypoxia (0% O 2 , 5% CO 2 , and 95% N 2 ) and maintained at 37°C by a heated water jacket. The isometric tension was continuously monitored using a PowerLab 4/26 system (AD Instruments, Inc., Colorado Springs, CO, United States), as previously described ( Yeh et al, 2018 ). All the vascular rings were stabilized and relaxed, with the resting tension adjusted to 5 mN.…”

“…DA smooth muscle cells in primary culture were all obtained from the DA of newborn Wistar rats as previous described ( Yeh et al, 2018 ). In brief, immediately after spontaneous delivery by the pregnant rat on the 21st gestational day, the newborn rats were killed by decapitation followed by taking down the DA.…”

Molecular Mechanisms Underlying Remodeling of Ductus Arteriosus: Looking beyond the Prostaglandin Pathway

“…Our previous study has demonstrated that in DA SMCs, Notch inhibition by DAPT can attenuate activations of ERK1/2 and JNK induced by Ang II [ 22 ], which reasoned its mechanisms underlying anti-proliferative and anti-migratory effects. In addition, we also found that BNP can exert anti-remodeling effects in the DA, with associated downregulation of ERK1/2 signaling [ 118 ].…”

Role of Extracellular Matrix in Pathophysiology of Patent Ductus Arteriosus: Emphasis on Vascular Remodeling

“…Yang et al further elaborated the role of peroxidasin in cardiac hypertrophy and found that peroxidasin mediated AngII-induced cardiac hypertrophy via the Nox2/VPO1/HOCl/ERK1/2 redox signaling pathway where Ang II increased the hypertrophy-related gene (BNP/ANF) expression [ 71 ]. Although the peroxidasin concept has not been established in PDA, inhibition of its downstream AngII with BNP has prevented proliferation and migration of DASMCs through reducing mitochondrial ROS production [ 72 ]. The overlapping pathways of peroxidasin in the DASMC phenotype suggest that peroxidasin can be a promising therapeutic target for clinical management of DA patency.…”