Angiogenesis and neurogenesis share similar growth factors and mediators, including the HiF1a VEGF signaling cascade, and neural guidance receptors-ligands. Proper cardiovascular remodeling in the embryo is dependent on the critical balance between these factors. Given the role for the hypoxia sensitive HiF1a-VEGF signaling cascade we investigated the consequences of hypoxic stress during embryogenesis. The clinical rationale is that prenatal hypoxic stress in humans is hypothesized to program for cardiovascular diseases (CVD) later in life. We investigated the consequences of prenatal hypoxic stress on cardiovascular remodeling in an experimental model using chick embryos and in human fetal growth restricted fetuses (FGR) with known episodes of hypoxia in utero. In the experimental model hypoxia caused aberrant remodeling of blood vessels, nerves and heart. We observed severe cardiomyopathy including pump dysfunction and left ventricular dilatation. These responses involved elevated expression of VEGF165, signaling through VEGFR2 and NRP1. Prenatal administration of sFlt1 or Sema3a rescued against these adverse effects. Analysis of human FGR fetuses revealed pump dysfunction concomitant with elevated expression of VEGF, and its receptors VEGFR-2 and NRP1 in cardiac biopsies. These data establish the VEGF/VEGFR2/NRP1 axis as the intrauterine modulator of fetal programming offering a novel strategy in the treatment of CVD.