Vasculogenesis is the mechanisms by which new blood vessels are formed. Yet, the molecular changes underlying human blood vessel formation and maturation remain unresolved. The placenta is an organ forming de novo during pregnancy to support fetal growth. Extensive vascular formation and maturation is therefore crucial to this organogenesis and a successful pregnancy outcome and aberrant placental vascular form and/or function may contribute to common obstetric complications that impair fetal well-being and lifelong cardiovascular health so, possibly compromise cardiovascular health [Leijnse et al., 2018; Burton et al., 2016]. In this study, we have performed proteomic analysis of human placental arteries at different stages of pregnancy to investigate the nature of protein changes underlying human blood vessel maturation. Following written informed consent (LREC 10/H0906/71), human placenta biopsies were obtained from 1st (7-12 weeks gestation, n=9) and 3rd (39-40 weeks gestation, n=7) trimesters of normal pregnancy. Chorionic plate arteries were isolated, homogenized, trypsin digested and analysed in triplicate with liquid chromatography mass spectrometry (LC-MS) using label-free SWATH (Serial Window Acquistion of All Theoretical spectra) acquisition [Ludwig et al., 2018; Rosenberger et al., 2014]. Proteins were quantified (≥5 fragment ions per peptide ion, ≥2 unique peptide ions per protein) in PeakView and differential protein abundance determined by unpaired t-test with multiple corrections FDR, followed by pathway analysis in STRING. 3586 proteins were quantified, with 1073 proteins differing between the 1st and the 3rd trimester (FDR 0.01 and >1.5-fold change). 482 proteins were up- and 591 down-regulated at term. Notable changes involved: (i) down-regulation of proteins regulating post-transcriptional processing (e.g. ribosomal and spliceosome-related proteins ); (ii) up-regulation of those involved in ECM/myofilament/cytoskeletal integrity; (iii) up-regulation of Serpin superfamily proteins. Of these proteins, many were found to display upward or downward trajectories of expression across the early pregnancy timeline examined of 7 to 12 weeks gestation indicative of processes required for a commitment to a mature vascular cell phenotype. Our study reveals an enormously dynamic proteomic milieu associated with human placental blood vessel maturation and provides a comprehensive characterization of the major underlying protein abundance changes. We identify key molecules (and processes) involved from early in pregnancy. We speculate that these molecules and pathways are also attractive candidates as markers of aberrant human vascular modelling whether that be in situations of (i) pregnancy complications accompanied by placental vasculopathy or (ii) systemic vascular diseases/injury resulting in smooth muscle de-differentiation (e.g. atherosclerosis).