**5. Conclusions**

Placentae from pregnancies a ffected by early-onset PE have increased total creatine content compared to normotensive controls. Although the current study did not identify changes to protein abundance, the metabolic stress of PE induced gene expression increases in creatine synthesizing enzymes and cytosolic creatine kinase. These initial observations sugges<sup>t</sup> that the PE placenta may adapt to perturbations in oxygen delivery and reduced ATP production at the site of the mitochondria by heightening its reliance on the creatine kinase circuit to stabilize bioenergetics. These processes should be further explored in the context of mitochondrial and endoplasmic reticulum stress, particularly AMPK activation, which has been shown in other tissues to up-regulate creatine metabolism in response to metabolic stress.

**Supplementary Materials:** Supplementary Materials can be found at http://www.mdpi.com/1422-0067/21/3/806/s1.

**Author Contributions:** All authors have read and agreed to the published version of the manuscript. Conceptualization, S.J.E. and R.J.S.; methodology, M.L.D.-T., G.M.K., D.L.C., C.R.B.; validation, formal analysis, S.J.E., A.K.M. and P.A.D.G.; investigation, S.J.E.; resources, P.M.; writing—original draft preparation, S.J.E.; writing—review and editing, P.M., P.A.D.G., A.K.M., M.L.D.-T., G.M.K., D.L.C., C.R.B., E.M.W., D.W.W., H.D., R.J.S.; supervision, E.M.W., D.W.W.; project administration, H.D.; funding acquisition, S.J.E., H.D., R.J.S., D.W.W. **Funding:** S.J.E. and M.L.D.-T. were NHMRC Early Career Fellows and H.D., an NHMRC Career Development Fellow during the completion of this study. G.M.K. (DE180100859) and C.R.B. (FT160100017) were supported by Australian Research Council Fellowships. A gran<sup>t</sup> from the NHMRC to H.D., D.W.W. and R.J.S. and the Victorian Government Infrastructure Support Fund to the Hudson Institute of Medical Research supported this work.

**Acknowledgments:** The authors would like to acknowledge the e fforts of all research support sta ff involved in the consenting and collecting of biological samples at the Royal Women's Hospital Melbourne, as well as the MHTP Medical Genomics Facility for providing sequencing services.

**Conflicts of Interest:** The authors declare no conflict of interest.
