Nitric oxide (NO), generated by NO synthase (NOS) enzymes, is an important bioactive molecule involved in the regulation of
several biological phenomena that are crucial for organogenesis, including gene expression, cell growth, matrix remolding, proliferation,
differentiation and apoptosis. The expression of NOS isoforms in embryonic tissues is temporally and spatially regulated, and disruption
of endogenous NO can lead to developmental defects. Maternal treatment with pan NOS inhibitors during early organogenesis caused severe
malformations of the axial skeleton. In utero exposure during the fetal period induced limb reduction defects of vascular origin.
Knock-out mice have been used to define the role of the various NOS isoforms on the origin of the abnormal development. Cardiovascular
malformations, limb reduction defects, reduced growth and reduced survival have been observed in knock-out mice with targeted disruption
of endothelial NOS (eNOS). Limited morphological changes were observed in mice lacking inducible NOS (iNOS) or neuronal
NOS n(NOS). Results obtained with in vitro studies suggest that optimal levels of NO are required for neural tube closure. Disregulation
of NO production was also recently proposed as a contributing mechanism in the origin of malformations associated with exposure to
known environmental teratogens, such as valproic acid, thalidomide, copper deficiency, and diabetes.
Keywords: Nitric oxide, nitric oxide synthase, nitric oxide synthase inhibitors, teratology, birth defects, limb defects, axial skeletal defects,
neural tube defects, cardiovascular defects.
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