(719.4) Prenatal Hypoxia is Associated with Coronary Artery Endothelial Dysfunction in Male and Female Offspring

Poster Board Number: E134

Nataliia Hula (University of Alberta), Mazhar Pasha (University of Alberta), Anita Quon (University of Alberta), Raven Kirschenman (University of Alberta), Christy-Lynn Cooke (University of Alberta), Floor Spaans (University of Alberta), Sandra Davidge (University of Alberta)

Introduction: Fetal hypoxia is a common consequence of complicated pregnancies and is linked to the development of cardiovascular (CV) dysfunction in the offspring. We showed an impaired cardiac function in adult prenatal hypoxia offspring, however, the mechanisms are not known. Coronary artery endothelial dysfunction has been shown to contribute to the development of cardiac dysfunction, however, whether endothelial function is impaired in coronary arteries of prenatal hypoxia offspring is unknown. We hypothesize that prenatal hypoxia leads to impaired coronary artery endothelial function in adult male and female offspring.

Methods: Pregnant Sprague-Dawley rats were exposed to normoxia (21% O2) or hypoxia (11% O2; p-Hyp) on gestational days 15-21 (term=22 days). Male and female offspring were aged to 9-9.5 months. Left anterior descending coronary arteries were isolated (n=5-7/group), and endothelium-dependent vasodilation to methylcholine (MCh) and endothelium-independent vasodilation to the nitric oxide (NO) donor sodium nitroprusside (SNP) were assessed by wire myography. To assess the contribution of endothelial vasodilation pathways, MCh-curves were performed in the presence/absence of inhibitors of nitric oxide synthase (L-NAME), prostaglandin H synthase ([PGHS]; meclofenamate), or small- and intermediate-conductance Ca2+-activated potassium channels (apamin and TRAM-34, respectively). Data were summarized as Emax (maximum vasodilation response), pEC50 (concentration required to produce 50% of Emax) or Area Under the Curve (AUC). Data were compared by two-way ANOVA (Sidak`s post hoc test); plt;0.05 was significant.

Results: Mch-induced vasodilation (Emax) was decreased in p-Hyp males (p=0.006) and females (p=0.032) compared to normoxia offspring. L-NAME completely inhibited vasodilation (AUC) in normoxia and p-Hyp males (plt;0.0001). In the female offspring, incubation with L-NAME completely inhibited vasodilation in the normoxia group (plt;0.0001), but to a lesser extent (Emax ~15%) in the p-Hyp offspring (plt;0.0001). In contrast, meclofenamate did not alter MCh-induced vasodilation (AUC) in males, while in females, meclofenamate increased vasodilation to MCh in the p-Hyp group only (p=0.04). Apamin and TRAM-34 did not alter responses to MCh in any of the groups. SNP sensitivity (pEC50) was decreased in p-Hyp females compared to normoxia controls (p=0.012), without changes in males.

Conclusions: Our data suggest that prenatal hypoxia leads to coronary artery endothelial dysfunction in male and female offspring. In prenatal hypoxia males, NO contribution to endothelium-mediated vasodilation was reduced. In females, prenatal hypoxia increased PGHS-dependent vasoconstriction and decreased smooth muscle sensitivity to NO. Understanding the mechanistic pathways involved in programming of CV disease may allow for the development of future prenatal and postnatal therapeutic interventions.

Canadian Institutes of Health Research; Stollery Childrenamp;rsquo;s Hospital Foundation and Alberta Womenamp;rsquo;s Health Foundation through the Women and Childrenamp;rsquo;s Health Research Institute; Stefan and Pelagia Wychowanec Graduate Scholarship; Motyl Graduate Studentship in Cardiac Sciences.