Smooth Muscle Cell Proliferation in the Ductus Arteriosus and the Descending Aorta, and Effects of Enalapril on SMC Proliferation in Perinatal Rats.

Abstract

ABSTRACT. This study was carried out to determine the proliferation profile of the smooth muscle cells (SMC) in the media of the ductus arteriosus (DA) and the descending aorta (Ao), and to examine the effects of the angiotensin-converting enzyme inhibitor enalapril on the proliferation of these cells in perinatal rats. The proliferating cell nuclear antigen (PCNA) index of the DA peaked in 19-day-old fetuses at 75%, and the index significantly declined in 20-day-old fetuses. The PCNA index of the Ao showed a similar profile until pups reached 1 day of age; however, the index of the Ao then increased in 3-day-old pups. The PCNA indices of the DA and Ao decreased significantly after maternal oral treatment with enalapril (10 mg/kg for 7 days), with a more marked decline in the DA than in the Ao. The PCNA indices of these vessels in 20-day-old fetuses were not altered by maternal treatment with enalapril. These results indicate that the SMC proliferation rate in the DA was similar to that in the Ao until pups reached the age of 1 day, and that the inhibitory effect of enalapril on the SMC proliferation was age-dependent and more prominent in the DA than in the Ao.-KEY WORDS: ductus arteriosus, enalapril, PCNA, proliferation, SMC.J. Vet. Med. Sci. 61(11): 1215-1218, 1999 investigated the PCNA labeling index to monitor the proliferating activity of the SMC, and we compared the effects of enalapril on SMC proliferation in the DA and the descending aorta (Ao). MATERIALS AND METHODSFemale Crj: Wistar rats, 10-12 weeks old at the time of mating, were used. They were maintained with commercial rat chow (CE-2, Clea Japan, Tokyo) and tap water ad libitum, and kept in a room at a temperature of 22 ± 3°C with a relative humidity of 55 ± 10%. Three females were placed with a male overnight, and were examined the next morning for the presence of sperm in a vaginal smear. The day when sperm was found was designated as day 0 of gestation, and the females were caged individually thereafter.To examine the age-related changes of the PCNA labeling indices of the DA and the Ao, fetuses were quickly removed from the uteri of mother rats from day 18 to day 21 of gestation, and 1 or 3 day-old newborn pups were obtained from witnessed deliveries. To examine the effect of enalapril on the PCNA labeling indices of these vessels, fetuses were obtained on day 19 or 20 of gestation from pregnant rats and were transplacentally administered enalapril (10 mg/kg) from day 12 or 13 for 7 consecutive days.Fetuses and newborn pups were decapitated, and then the thoracic cavity was opened and immersed in fresh fixative fluid. Fixation was performed in 100% ethanol for 24 hr, and the fixed materials were then freed of alcohol by treatment with xylene, embedded in Paraplast (Sherwood Closure of the ductus arteriosus (DA) is one of the most critical events for adaptation of mammals to extrauterine life. The ductal closure after birth occurs in two stages, i.e., initial closure and anatomical closure. Initial closure is brought about by contraction of th...

Gamma-secretase Inhibitor Prevents Proliferation and Migration of Ductus Arteriosus Smooth Muscle Cells through the Notch3-HES1/2/5 Pathway

“…Ang II has been implicated as a mediator in the processes of DA remodeling due to its proliferative effects 17-19. To determine whether DAPT attenuates Ang II-induced DASMC proliferation, we first examined the viability of PASMCs by the MTT assay.…”

“…For example, our recent study has demonstrated that through reducing ROS production, a new generation calcium channel blocker can inhibit proliferation and migration of aortic vascular SMCs 18. We also found that anti-proliferative and anti-migratory effects of B-type natriuretic peptide on PASMCs are associated with reduced ROS production by mitochondria and NADPH oxidase 17. How Notch signaling affects the redox state has not been well understood.…”

“…In this context, we examined if γ-secretase inhibitor (DAPT), an inhibitor of Notch signaling, can prevent DASMC proliferation and migration induced by angiotensin-II (Ang II), a mediator implicated in DA remodeling 17-19, and further explored the potential mechanisms underlying these effects.…”

Role of Nitric Oxide in Regulating the Ductus Arteriosus Caliber in Fetal Rats.

“…In fact, the expression of SM2 was observed only in the SMCs of fetal DA in rabbits [14] and mice [9]. Although the expression of SM2 in the DA has not been studied in rats, SMCs of the DA in 18-and 19-day-old fetuses showed high levels of proliferating activity as revealed by a frequency of the proliferating cell nuclear antigen-positive cells [23]. The high level of proliferating activity of the SMCs was dramatically decreased in the DA of 20-and 21-day-old fetuses [23], suggesting that 19 days of gestation may be the critical stage for the maturation of the DA.…”

“…Although the expression of SM2 in the DA has not been studied in rats, SMCs of the DA in 18-and 19-day-old fetuses showed high levels of proliferating activity as revealed by a frequency of the proliferating cell nuclear antigen-positive cells [23]. The high level of proliferating activity of the SMCs was dramatically decreased in the DA of 20-and 21-day-old fetuses [23], suggesting that 19 days of gestation may be the critical stage for the maturation of the DA. Considering the above together with reports that the endogenous NO production is increased in pregnant rats [10], and then decrease at term [26], we considered that the DA in 19-day-old fetuses might have shown a pronounced response to L-NAME due to both SMC maturation and NO production.…”