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 down-regulates fetal adenosine A2A 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. Methods Gestational day 11.5 pregnant mice were exposed to hypoxia (45 second duration followed by 10 minutes 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 2nd and 3rd 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 A2A receptor antagonist, but not an adenosine A1 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 A2A receptor inhibition during primary cardiovascular morphogenesis.

Maternal Caffeine Consumption during Pregnancy and Risk of Low Birth Weight: A Dose-Response Meta-Analysis of Observational Studies

“…When caffeine acts as an antagonist of adenosine receptor, adenosine is unable to regulate the local blood flow during hypoxia [ 9 ]. The acute maternal hypoxia can negatively impact the fetal cardiovascular function and fetal growth [ 45 ]. Also, when PDE is inhibited by caffeine, the levels of cyclic adenosine monophosphate (cAMP) will be increased because PDE degrades cAMP, which may interfere with fetal growth.…”

Validating the Paradigm That Biomechanical Forces Regulate Embryonic Cardiovascular Morphogenesis and Are Fundamental in the Etiology of Congenital Heart Disease

“…Exploration of CV functional maturation and the relationships between function, biomechanics, and morphogenesis in mammalian embryos began with the adaptation of hemodynamic measurement techniques developed for the exposed chick embryo with novel methods to ensure normal maternal oxygenation during sedation, normal embryo temperature, maternal oxygenation, and undisturbed maternal–embryo coupling ( Figure 15 ) [ 232 , 233 , 234 ]. Ultrasound proved very useful in quantifying basic measures of chamber dimensions, ventricular function, and blood flow velocities in normal mouse embryos [ 232 , 235 , 236 , 237 , 238 , 239 , 240 , 241 , 242 ], in embryos with trisomy 16 [ 243 ], and embryos exposed to maternal caffeine ( Figure 16 ) [ 244 , 245 ]. Murine embryonic dorsal aortic flow velocity measurement revealed reduced diastolic forward flow consistent with increased murine placental resistance compared to similar stages in human development [ 239 , 246 , 247 , 248 , 249 , 250 , 251 , 252 ] and confirmed the dependence of cardiac output on stage dependent normal heart rates and activation sequence [ 253 ] and the dependence of arch morphogenesis on genetic factors [ 254 ].…”

Morphological features of atrial myocardium embryonic development and its changes caused by hypoxia effect

“…A wide range of birth defects, the formation of which occurs in the early stages of cardiogenesis is evidence of the vulnerability of the embryonic heart during this period. This necessitates the use of a significant arsenal of research methods: light microscopy (Ream et al, 2008), immunohistochemistry (Garlanda et al, 1997Azar et al, 2003;Dong & Thompson, 2006;Tonne et al, 2011), electron microscopy (Schaper et al, 1985;McKenzie et al, 1994;Zhang & Pasumarthi, 2007;Oxford et al, 2011;Cury et al, 2012), microcomputer tomography (Nieman & Turnbull, 2010;Gilbert et al, 2012), ultrasound microscopy (Araujo Júnior et al, 2012;Hernandez-Andrade et al, 2012;Hongmei et al, 2012;Gindes et al, 2012), echocardiography (Choi et al, 2013Lee &Won, 2013), confocal microscopy (Sands et al, 2005), and three-dimensional visualization (Momoi et al, 2012). Each method has its advantages and disadvantages.…”