Calcineurin signaling in avian cardiovascular development.

Experiments were initiated in avian embryos to determine the embryonic expression of calcineurin protein phosphatase isoforms as well as to identify developmental processes affected by inhibition of calcineurin signal transduction. Chicken calcineurin A alpha (CnAalpha) and calcineurin A beta (CnAbeta) are differentially expressed in the developing cardiovascular system, including primitive heart tube and valve primordia. Inhibition of calcineurin signaling by cyclosporin A (CsA) treatment in ovo resulted in distinct cardiovascular malformations, depending on the timing and localization of treatment. Initial formation of the heart tube was apparently normal in embryos treated with CsA from embryonic day (E)1 to E2, but hallmarks of heart failure were apparent with treatment from E2 to E3. Vascular defects were apparent in whole embryos treated on either day, but local administration of CsA directly to the forming vessels on E2 did not inhibit blood vessel formation. This observation supports an indirect effect of calcineurin inhibition on angiogenic remodeling as a result of compromised heart development. Together these studies are consistent with multiple roles for calcineurin signaling in the developing cardiovascular system.