Hsp90/Enos Interactions Contribute To Maturational And Chronic Hypoxia-Induced Changes In Pulmonary Vascular Reactivity In Newborn Pigs

Hsp90 is a molecular chaperone involved in regulating eNOS signaling. Concomitant with enhanced NO production, the association of Hsp90 with eNOS increases upon stimulation with agonists such as Acetylcholine (ACh). The role of Hsp90/eNOS interactions in maturational changes in pulmonary vascular reactivity is unclear. Moreover, there are no data on Hsp90/eNOS interactions in newborns with chronic hypoxia-induced pulmonary hypertension. Methods: Piglets were raised in normoxia or hypoxia from day of life 2 to 6. A cannulated artery technique was used to measure ACh responses in resistance pulmonary arteries (RPAs). A coprecipitation technique was used to assess Hsp90/eNOS interactions in RPAs. Results: ACh induced a greater dilation in RPAs from 6-day old pigs raised in normoxia(102+/−5%) than in RPAs from 2 day old pigs (80+/−8%). ACh stimulated a greater increase in Hsp90/eNOS coprecipitation in RPAs from 6-day old pigs raised in normoxia (190+/−64%) than those from 2 day old pigs (18+/−7%). ACh induced dilation was reduced in RPAs from 6-day old pigs raised in hypoxia (30+/−22%) compared with 6-day old pigs raised in normoxia. ACh stimulation failed to increase Hsp90/eNOS coprecipitation in RPAs from pigs raised in hypoxia. Conclusions: Hsp90/eNOS interactions mature during the first week of life and contribute to the enhanced pulmonary vascular responses to NO-dependent agonists observed with advancing postnatal age. Chronic hypoxia alters pulmonary vascular reactivity in part by disrupting the normal maturational enhancement of Hsp90/eNOS interactions. Manipulating Hsp90/eNOS interactions could augment pulmonary vascular NO activity in newborns with chronic hypoxia-induced pulmonary hypertension. Funding: NIH RO1HL075511 and RO1HL068572