Abstract 2176: Prenatal Hypoxic Stress Causes Cardiomyopathy Involving Cardiomyocyte Specific Vascular Endothelial Growth Factor Signaling
introduction Cardiovascular diseases in adulthood can be programmed in utero by prenatal stresses. The mechanism is unknown but may involve hypoxia. We assessed the hypothesis that prenatal hypoxic stress programs for cardiomyopathy.
methods We measured umbilical artery blood levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), an indicator of heart failure, in 15 neonates diagnosed hypoxic and growth restricted or normal. Cardiac biopsies from 10 patients who died of intrauterine hypoxia or congenital syndromes were stained for glycogen and apoptosis. Expression of the hypoxia-sensitive cytokine vascular endothelial growth factor (VEGF) and its receptors VEGF receptor-2 (VEGFR-2) and neuropilin-1 (NRP1) was assessed by immunohistochemistry. The cardiac response to hypoxia was further defined in a chick embryo model.
results NT-proBNP levels were elevated in hypoxic (n=5) compared to normoxic (n=10) neonates (3500±68 vs 2200±43 fmol/mL; p<0.001). Cardiac biopsies of hypoxic human fetuses (n=5) displayed histological signs of heart failure, including glycogen accumulation and enhanced cardiomyocyte apoptosis, and demonstrated increased expression of VEGF-A, VEGFR-2 and NRP1 in cardiomyocytes as compared with normoxic fetuses (n=5). Hypoxic chick embryos showed a dilated left ventricle with impaired contractility and histological signs of heart failure at birth. Dilated cardiomyopathy persisted into adulthood. Cardiomyocyte specific expression of VEGF-A, VEGFR-2 and NRP1 was also significantly elevated in hypoxic chick embryo hearts. Only VEGF165, not VEGF121 or placental growth factor-1, exerted direct negative inotropic effects on cardiomyocytes, which was abolished by blocking VEGFR-2 signaling. Prenatal treatment with the VEGF-A scavenger soluble VEGF receptor-1 rescued from progression to cardiomyopathy.
conclusions Prenatal hypoxia is a risk factor for heart failure and our study establishes the VEGF/VEGFR-2 axis as the intrauterine modulator of fetal programming of cardiomyopathy, offering a novel strategy focused on prenatal identification and therapy.