Reduction of Maternal Adrenal Steroids Results in Increased VEGF Protein Without Increased eNOS in the Ovine Placenta

Fetal sheep studies have shown that reduced maternal cortisol or aldosterone levels alter placental morphology, with a reduction in placental blood flow. We have now tested the hypothesis that changes in placental morphology with relative adrenal hypoadrenalism are associated with changes in vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS). Four groups of late gestation pregnant ewes with singleton fetuses were studied; controls (intact adrenals), normal cortisol and aldosterone (ewes adrenalectomized and replaced with normal cortisol and aldosterone levels), low cortisol (ewes adrenalectomized and replaced with low cortisol levels), and low aldosterone (ewes adrenalectomized and replaced with low aldosterone levels). The placenta was categorized into A, B, C or D type placentomes. There were significantly more B and C type placentomes in the adrenalectomized groups than in controls. Overall, B types had more VEGF mRNA than A types. VEGF protein levels corresponding to a 23 kDa band were highest in low aldosterone animals in A and C type placentomes. VEGF protein levels corresponding to a 47 kDa band were higher in C type placentomes than A types; protein levels were also higher overall in low cortisol animals compared to controls. Fetoplacental eNOS protein levels were lower in the adrenalectomized groups than in controls. In conclusion, our results indicate that increases in cotyledonary VEGF164 protein were associated with fetal tissue overgrowth in the placenta when the pregnancy-induced increase in adrenal steroids was prevented in the ewe. However, cotyledonary eNOS protein was suppressed with reduced maternal adrenal steroids, which is consistent with the reduced placental perfusion previously observed in this model.