Placenta-targeted treatment with nMitoQ prevents an endothelin receptor A pathway cardiac phenotype observed in adult male offspring exposed to hypoxia in utero

Prenatal hypoxia is associated with an enhanced susceptibility to cardiac ischemia/reperfusion (I/R) injury in adult offspring, however the mechanisms remain to be fully investigated. Endothelin-1 (ET-1) is a vasoconstrictor that acts via endothelin A (ETA) and endothelin B (ETB) receptors and is essential in maintaining cardiovascular (CV) function. Prenatal hypoxia alters the ET-1 system in adult offspring possibly contributing to I/R susceptibility. We previously showed that ex vivo application of ETA antagonist ABT-627 during I/R prevented the recovery of cardiac function in prenatal hypoxia-exposed males but not in normoxic males nor normoxic or prenatal hypoxia-exposed females. In this follow-up study we examined whether placenta-targeted treatment with a nanoparticle encapsulated mitochondrial antioxidant (nMitoQ) during hypoxic pregnancies could alleviate this hypoxic phenotype observed in adult male offspring. We used a rat model of prenatal hypoxia where pregnant Sprague-Dawley rats were exposed to hypoxia (11% O2) from gestational days (GD) 15-21 after injection with 100μL saline or nMitoQ (125 μM) on GD 15. Male offspring were aged to 4 months and ex vivo cardiac recovery from I/R was assessed. Offspring born from hypoxic pregnancies treated with nMitoQ had increased cardiac recovery from I/R in the presence of ABT-627 compared to their untreated counterparts where ABT-627 prevented recovery. Cardiac ETA levels were increased in males born from hypoxic pregnancies with nMitoQ treatment compared to saline controls (Western blotting). Our data indicate a profound impact of placenta-targeted treatment to prevent an ETA receptor cardiac phenotype observed in adult male offspring exposed to hypoxia in utero.