Prenatal alcohol exposure (PAE) impairs the “placenta–brain” axis that controls foetal brain angiogenesis. Placental growth factor (PlGF) has been identified as a proangiogenic messenger between these two organs. CD146, a partner of the VEGFR-1/2 signalosome, is involved in placental angiogenesis and exists as a soluble circulating form. The aim of the study was to investigate whether placental CD146 may contribute to brain vascular defects described in foetal alcohol spectrum disorder. In human placenta, the CD146 is expressed in developing villi and membrane and soluble CD146 forms are differentially expressed from the first trimester to term. In the mouse placenta, a similar expression pattern of CD146 was found. CD146 immunoreactivity was detected in the labyrinth zone and colocalized with CD31-positive endothelial cells. Significant amounts of soluble CD146 were quantified in foetal blood and decreased after birth. In the foetal brain, the CD146 membrane form colocalized with microvessels. At a pathophysiological level, PAE induced marked dysregulation of CD146 expression: soluble CD146 decreased in both placenta and foetal blood, whereas it increased in the foetal brain. The expression of members of the CD146 signalosome, such as VEGFR2 and PSEN, was differentially impaired between the two organs. At a functional level, targeted repression of placental CD146 by in utero electroporation of CRISPR/Cas9 plasmids resulted in a decrease in cortical vessel density, a loss of radial vascular organization and a reduced oligodendrocyte density, similar to PAE. These data support that placental CD146 contributes to the proangiogenic “placenta–brain” axis and the oligo-vascular development.