Novel roles of purinergic signaling for altitude-associated fetal growth restriction

PROJECT SUMMARY The hypoxia of high-altitude (HA, >2500 m) increases the frequency of fetal growth restriction (FGR) 3-fold. Reduced uteroplacental perfusion is an important contributor to altitude-associated FGR and is determined, in part, by reduced vasodilatory sensitivity of the myometrial (MyoA) and uterine arteries (UtA). It is therefore vital to define mechanisms that defend uteroplacental blood flow and fetal growth under hypoxic conditions. Using a metabolomic approach we have found maternal and fetal circulating nucleotide metabolites belonging to the purinergic signaling pathway (i.e., adenosine, ADP, AMP, ATP, UDP, UDP-glucose) to differ between HA and low altitude (400 m) in Bolivia, we also observed differences in nucleotide abundance when comparing FGR with uncomplicated pregnancies. Furthermore, our preliminary functional data showed that adenosine vasodilates MyoA and chorionic plate arteries (CPA), the latter are fetoplacental vessels important for the regulation of fetal circulation. In addition, confirming the role of these nucleotides, purinergic receptor agonists known to act as vasconstrictors evoked vasoconstriction in CPA. Thus, we uteroplacental response to nucleotides that elicit vasoconstriction at hypothesize that t he residence blunts vasodilatory responses to vasorelaxant nucleotide metabolites and enhances the vasoconstrictive HA compared to LA. hypoxia of HA Aim 1 will establish the effect of HA pregnancy on the maternal plasma metabolome by mass spectrometry, determine the effect of vasoactive metabolites that differ between altitudes on MyoA vasoreactivity by myography and, using a targeted approach, determine the relationship between the maternal metabolome and UtA blood flow. Aim 2 will determine the effect of HA on the fetal circulation metabolome, the regulation of CPA vasoreactivity by vasoactive nucleotides, and establish the relationship of such effects for fetal oxygenation and growth. In both aims, we will measure protein expression in MyoA and CPA of key purinergic receptors, ectonucleotidases, and enzymes known to participate in purinergic signaling. Our findings will provide the basis for our future research to identify molecular pathways that integrate uteroplacental and fetoplacental perfusion and cellular metabolism during pregnancy to maintain fetal growth.