Cardiovascular overexpression of transforming growth factor-beta(1) causesabnormal yolk sac vasculogenesis and early embryonic death

Transforming growth factor-beta(1) (TGF-beta(1)) is expressed in the adult and embryonic vasculature; however, the biological consequences of increase d vascular TGF-beta(1) expression remain controversial. To establish an exp erimental setting for investigating the role of increased TGF-beta(1) in va scular development and disease, we generated transgenic mice in which a cDN A encoding a constitutively active form of TGF-beta(1) is expressed from th e SM22 alpha promoter. This promoter fragment directs transgene expression to smooth muscle cells of large arteries in late-term embryos and postnatal mice, We confirmed the anticipated pattern of SM22 alpha-directed transgen e expression (heart, somites, and vasculature of the embryo and yolk sac) i n embryos carrying an SM22 alpha-beta-galactosidase transgene, SM22 alpha-b eta-galactosidase transgenic mice were born at the expected frequency (13%) ; however, nearly all SM22 alpha-TGF-beta(1) transgenic mice died before E1 1.5. SM22 alpha-TGF-beta(1) transgenic embryos identified at E8.5 to E10.5 had growth retardation and both gross and microscopic abnormalities of the yolk sac vasculature. Overexpression of TGF-beta(1) from the SM22 alpha pro moter is lethal at E8.5 to E10.5, most likely because of yolk sac insuffici ency. Investigation of the consequences of increased vascular TGF-beta(1) e xpression in adults may require a conditional transgenic approach. Moreover , because the SM22 alpha promoter drives transgene expression in the yolk s ac vasculature at a time when embryonic survival is dependent on yolk sac f unction, use of the SM22 alpha promoter to drive expression of "vasculoacti ve" transgenes may be particularly likely to cause embryonic death.