Pulmonary arterial vasoreactivity changes due to the birth transition and the influence of high altitude gestation in lambs

Abstract

Gestation and birth at high altitude is a risk factor in the development of pulmonary hypertension (PH) in the newborn, which afflicts approximately 6 in every 1000 term births. Prior to birth the pulmonary vasculature has high resistance and low flow, however during the transition at birth the resistance drops rapidly allowing for increases in flow. Previous evidence illustrates that high altitude gestation hinders this transition process, which leads to PH. To begin to understand this process in more depth and the etiology associated with the development of PH with birth at high altitude we tested the hypothesis that high altitude gestation would increase arterial reactivity and decrease vasodilatory capacity in lambs going through birth transition. This was examined in wire myography studies performed on pulmonary arteries isolated from near‐term (139 to 141 days gestation, term = 145) fetal lambs that gestated at high altitude (3801 m) for 110+ days or at low altitude (700 m). Ewes were anesthetized with isoflurane and lambs were delivered by C‐section and immediately sacrificed or underwent experimentally‐induced birth transition. Birth‐transition lambs were instrumented with an arterial catheter and endotracheal tube and delivered via C‐section, anesthetized with ketamine (1 mg/kg boluses every hour), and mechanically ventilated with an FiO2 of 30% for three hours. Arterial PO2 and PCO2 were maintained within normal newborn ranges by adjusting tidal volumes and ventilator rate. Lungs were harvested from near term and birth transition lambs and arteries isolated for wire myography. In the wire myography studies evaluations were made of electromechanical coupling by contracting arteries with 125 mM KCl (High K), pharmacomechanical coupling by exposing arteries to additive concentrations of serotonin (5‐HT), and vasodilatory capacity with S‐Nitroglutathione (gSNO), a biologically relevant source of NO. High altitude gestation reduced arterial reactivity to High K and 5‐HT in near term fetuses while birth transition reduced arterial reactivity in low altitude but not high altitude animals. The potency for 5‐HT was diminished in animals that went through birth transition. Dilatory capacity to gSNO was impaired by high altitude gestation but unaffected by the birth transition. These data suggest that the birth transition preferentially reduces constrictor pathways and that dilatory pathways are well developed at the time of birth. High altitude gestation then reduces both contractile as well as dilatory capacities, paralleling other data suggesting high altitude gestation causes cellular immaturity.Support or Funding InformationSupported in part by NIH grant HD083132 (ABB), HD098477 (SMW)