| Summary: | <p><i>Background:</i> Preeclampsia is a placental disease, resulting in maternal hypertension and multi-organ impairment. The relationship between placental pathology and the widespread inflammation and endothelial dysfunction in preeclampsia is incompletely characterised. Mismatch between placental nutrient supply and fetal demands induces stress in the syncytiotrophoblast, the placental layer in contact with maternal blood. Such stress alters the content and release of extracellular vesicles (STB-EVs) into the maternal circulation. I have previously shown 5’-tRNA fragments (5’-tRFs) constitute the majority of small RNA in STB-EVs in healthy pregnancies. 5’-tRFs are produced in response to stress. In this thesis, I hypothesise STB-EV 5’-tRFs release might change in early-onset preeclampsia. I aim to 1) characterise STB-EV 5’-tRFs in normal pregnancy and preeclampsia; 2) investigate STB-EV tRFs in maternal blood; 3) evaluate tRFs as circulating biomarkers in preeclampsia; 4) explore functional activity of STB-EV tRFs in preeclampsia dysfunctional cells.</p>
<p><i>Methods:</i> Placentas from eight cases and six controls were perfused, comparing smallRNA sequences from STB-EVs using various bioinformatic approaches. EVs, STB-EVs and total RNA were isolated from different plasma samples and tRFs quantified using qPCR. The actions of the most abundant preeclampsia-dysregulated 5’-tRFs were investigated in monocytes, macrophages and endothelial cells.</p>
<p><i>Results:</i> 5’-tRFs constitute the majority of small RNA in STB-EVs from both preeclampsia and normal pregnancies. >4000 small RNA fragments are differentially expressed in preeclampsia STB-EVs. Preeclampsia-dysregulated 5’-tRFs are detectable in maternal plasma, where a placentally-derived load circulates. 5’-tRFs do not currently represent blood biomarkers for preeclampsia. The most abundant preeclampsia-upregulated small RNA, 5’-tRF-Glu-CTC, induces inflammation in macrophages but has no direct effect on monocytes or endothelial cells. The conditioned media from 5’-tRF-Glu-CTC-activated macrophages reduces endothelial nitric oxide synthase expression and increases adhesion molecule expression in endothelial cells.</p>
<p><i>Conclusions:</i> STB-EV tRFs are placental endocrine signals which contribute to the pathogenesis of preeclampsia at a molecular level.</p>
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