Normal fetal development depends on adequate placenta blood flow. Regulation of fetoplacental blood flow has been examined in the perfused cotyledon in vitro and, in this model, lowering oxygen tension raises vascular resistance. The mechanism of regulation of smooth muscle contraction by oxygen in fetoplacental vessels is poorly understood. Here we examine the effects of oxygen on agonist-induced constriction of placental chorionic plate arteries and relaxation to nifedipine, a L-type voltage-gated Ca2+ channel blocker.
Term placentae (n = 18) were obtained from uncomplicated pregnancies. Chorionic plate arteries (intraluminal diameter 312 ± 15 µm; n = 76) were mounted on a wire myograph under standard conditions. Vessels were normalised as described previously (Wareing et al. 2002). Constriction profiles were produced to KCl (15-60 mM) or endothelin (ET-1; 10-10-2 X 10-7 M) and then paired vessels were constricted with sub-maximal doses of KCl (45 mM) or ET-1 (1.19 X 10-7 M) and relaxation assessed to incremental doses of nifedipine (10-8-10-4 M applied for 2 min) or DMSO (diluent). Relaxation was expressed as a percentage of the time matched controls. Experiments were performed at 21 % (air/5 %CO2) or 2 % (N2/5 %CO2) oxygen.
The maximum constriction to KCl was not affected by reducing oxygen from 21 % to 2 % (mean ± S.E.M.: 3.6 ± 0.4kPa and 3.6 ± 0.3kPa respectively). Constriction to 45 mM KCl in 21 % oxygen was almost completely abolished by 10-4M nifedipine (relaxation = 91.3 ± 1.7% Fig. 1A) indicating that KCl-induced constriction is mediated by nifedipine-sensitive Ca2+ channels. Although reducing oxygen to 2 % did not affect the maximum relaxation with nifedipine (88.9 ± 3.2 %), there was a significant increase in sensitivity to nifedipine at the lower oxygen tension (P = 0.02 two way ANOVA; Fig. 1A). The maximum constriction to ET-1 was higher in 2 % than 21 % oxygen (9.0 ± 0.5kPa and 7.1 ± 0.7kPa respectively: P < 0.05 unpaired t test). The sub-maximal constriction to ET-1 in 21 % oxygen was only partially inhibited by 10-4M nifedipine (relaxation = 57.3 ± 12.9% Fig. 1B) indicating that nifedipine-sensitive and insensitive mechanisms contribute to constriction with ET-1. Reducing oxygen tension to 2 % did not affect the maximum relaxation with nifedipine (71.5 ± 11.3 %) but induced a significant increase in nifedipine sensitivity (P = 0.014 two way ANOVA; Fig. 1B ).
This study demonstrates that nifedipine-sensitive mechanisms have a role in the constriction of chorionic plate small arteries in response to KCl and ET-1. We propose:(1) constriction to ET-1 and nifedipine-induced relaxation is oxygen sensitive and (2) oxygen sensitivity is mediated by L-type voltage-gated Ca2+ channels which are activated by low oxygen tension.
This work was funded by Tommy’s the Baby Charity
