Elucidating the mechanisms underlying maternal vascular adaptation to pregnancy

RAMON LORCA -

Dr. Lorca received his PhD in Physiological Sciences from the Pontifical Catholic University of Chile in 2008. He did postdoctoral training at the University of Iowa and Washington University in St. Louis in Dr. Sarah England’s lab, where he studied the role of potassium channels in vascular and uterine function during pregnancy. He is currently an instructor in the Department of Obstetrics and Gynecology at the University of Colorado Anschutz Medical Campus. Dr. Lorca’s research interests focus on the regulation of vascular smooth muscle cell excitability during pregnancy and how impaired maternal vascular function impacts fetal growth.

PRESENTATION -

During pregnancy, fetal growth and development require a progressive increase in maternal uteroplacental circulation. Insufficient uteroplacental perfusion contributes to adverse pregnancy outcomes such as intrauterine growth restriction (IUGR), preeclampsia, and fetal loss. The chronic hypoxia of high-altitude residence (>2500 m of elevation) raises the incidence of IUGR and preeclampsia threefold, due to a lesser rise in uterine artery blood flow across gestation, suggesting that chronic hypoxia impairs uterine vascular adaptation to pregnancy. However, not all pregnancies at high altitude are affected, populations from Andean or Tibetan ancestry are protected from altitudinal reductions in uterine artery blood flow and fetal growth compared to their shorter-term (European or Han) counterparts. In Andeans, a single nucleotide polymorphism located near PRKAA1, encoding the catalytic subunit of the AMP-activated kinase (AMPK), was positively associated with birth weight and uterine artery diameter at high altitude. AMPK is a metabolic sensor that is activated by ATP depletion, hypoxia, and other stressors and has potent vasodilator effects. Thus, we studied the mechanisms by which AMPK activation vasodilates resistance (myometrial) arteries in the pregnant human uterus from high- and moderate-altitude residents in Colorado whose pregnancies were uncomplicated and those who were diagnosed with IUGR. A critical barrier for reducing the adverse outcomes associated with IUGR is our lack of understanding of the molecular and physiologic mechanisms responsible for the diminished uteroplacental blood flow necessary to support normal fetal growth and development. Our research may lead to the identification of novel molecular targets, such as AMPK, for the treatment of IUGR.