Homocysteine inhibits extra-embryonic vascular development in the avian embryo

A strong association exists between pregnancy loss and maternal elevations of the sulfur-containing amino acid, homocysteine. Because extra-embryonic vascular growth is critical to maintaining a normal pregnancy, we examined the effects of homocysteine on vessel development by exposing avian embryos to exogenous homocysteine during critical periods of vascular growth. These experiments demonstrated that homocysteine significantly reduced survival and decreased angiogenesis in the extra-embryonic vasculature. Homocysteine was also found to reduce mRNA and protein expression of vascular endothelial growth factor (VEGF), a key molecule for vascular development. Moreover, in cultured human umbilical vein endothelial cells, homocysteine increased the synthesis of nitric oxide, an important regulatory molecule for VEGF. Inhibiting the homocysteine-induced up-regulation of nitric oxide restored normal VEGF expression and vascular development. These results suggest that homocysteine may impair the development of the extra-embryonic vasculature by reducing the expression of VEGF.