Maternal hypoxia and caffeine exposure depress fetal cardiovascular function during primary organogenesis

Abstract

Aims: Hypoxia is known to influence cardiovascular (CV) function, in part, through adenosine receptor activation. We have shown in a mouse model that during primary cardiac morphogenesis, acute maternal hypoxia negatively affects fetal heart rate, and recurrent maternal caffeine exposure reduces fetal cardiac output (CO) and downregulates fetal adenosine A(2A) receptor gene expression. In the present study, we investigated whether maternal caffeine dosing exacerbates the fetal CV response to acute maternal hypoxia during the primary morphogenesis period.

Material and methods: Gestational-day-11.5 pregnant mice were exposed to hypoxia (45 s duration followed by 10 min of recovery and repeated 3 times) while simultaneously monitoring maternal and fetal CO using high-resolution echocardiography.

Results: Following maternal hypoxia exposure, maternal CO transiently decreased and then returned to pre-hypoxia baseline values. In contrast to a uniform maternal cardiac response to each exposure to hypoxia, the fetal CO recovery time to the baseline decreased, and CO rebounded above baseline following the second and third episodes of maternal hypoxia. Maternal caffeine treatment inhibited the fetal CO recovery to maternal hypoxia by lengthening the time to CO recovery and eliminating the CO rebound post-recovery. Selective treatment with an adenosine A(2A) receptor antagonist, but not an adenosine A(1) receptor antagonist, reproduced the altered fetal CO response to maternal hypoxia created by caffeine exposure.

Conclusions: Results suggest an additive negative effect of maternal caffeine on the fetal CV response to acute maternal hypoxia, potentially mediated via adenosine A(2A) receptor inhibition during primary cardiovascular morphogenesis.

Figure 1. Maternal hemodynamic effects of repeated maternal hypoxia with adenosine receptor antagonists

Dams were repeatedly exposed to 100% nitrogen for 45 seconds followed by a 10 to 20 minute recovery period.(A): Maternal heart rate, (B): Maternal stroke volume, (C): Maternal cardiac output.

Figure 2. Maternal blood pressure responses to hypoxia, caffeine, and Adenosine receptor antagonist treatments

Maternal blood pressure was consecutively measured using a tail cuff blood pressure system. There were no significant differences in one-minute mean maternal blood pressure among the four groups.

Figure 3. Fetal hemodynamic effects of repeated maternal hypoxia with adenosine receptor antagonists

Dams were repeatedly exposed to 100% nitrogen for 45 seconds followed by a 10 to 20 minute recovery period.(A): Fetal heart rate, (B): Fetal stroke volume, (C): Fetal cardiac output.

Figure 4. Fetal dorsal aortic flow recovery time to baseline following hypoxia, caffeine, and Adenosine receptor antagonist treatments

Recovery time was defined as the time from the start of hypoxia to the point in time when fetal dorsal aortic flow recovered to the baseline. If no restoration to the baseline occurred, the recovery time was defined as 10 minutes.

Figure 5. Mean percentage changes in fetal cardiac output following the onset of hypoxia

The mean percentage change of the fetal cardiac output after the first hypoxia in the CPT group was higher than that in the control group. Control and CPT groups showed a similar trend of changes in fetal CO, while Caffeine and adenosine A2A antagonist, MSX-3, treated group did not recover the fetal CO to the baseline levels following 2^nd and 3^rd hypoxia exposure.

Figure 6. Schematic diagram of maternal hypoxia and caffeine exposure effects on utreoplacental and fetoplacental circulations

Maternal hypoxia increases adenosine concentration within uteroplacental (maternal) and fetoplacental (fetal) circulations in which both adenosine A₁ and A_2A receptors are activated (panel A). Adenosine A₁ receptor activation decreases maternal and fetal heart rate and cardiac output (initial hypoxia response), and A_2A receptor activation increases uterine and fetal arterial blood flow by vasodilation with relatively decreased placenta vascular flow (vasoconstriction) resulting in fetal cardiac output recovery (recovery phase of hypoxia). Caffeine, a non-selective adenosine antagonist, inhibits adenosine receptor activation. While initial decrease in cardiac output of utero- and feto-placental circulations by combined hypoxia and caffeine exposure is less than hypoxia only, inhibition of adenosine A_2A receptor by caffeine leads to decrease in uterine and fetal arterial blood flow (inhibition of vasodilation) and blood flow steal to the placental vasculature (blood flow redistribution within fetoplacental circulation by placental vasodilation,) resulting in failure in cardiac output recovery of fetoplacental circulation (panel B).