Cardiovascular overexpression of transforming growth factor-β₁ causes abnormal yolk sac vasculogenesis and early embryonic death

Transforming growth factor-β₁ (TGF-β₁ is expressed in the adult and embryonic vasculature; however, the biological consequences of increased vascular TGF-β₁ expression remain controversial. To establish an experimental setting for investigating the role of increased TGF-β₁ in vascular development and disease, we generated transgenic mice in which a cDNA encoding a constitutively active form of TGF-β₁ is expressed from the SM22α 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 SM22α-directed transgene expression (heart, somites, and vasculature of the embryo and yolk sac) in embryos carrying an SM22α-β-galactosidase transgene. SM22α-β- galactosidase transgenic mice were born at the expected frequency (13%); however, nearly all SM22α-TGF-β₁ transgenic mice died before E11.5. SM22α-TGF-β₁ 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-β₁ from the SM22α promoter is lethal at E8.5 to E10.5, most likely because of yolk sac insufficiency. Investigation of the consequences of increased vascular TGF-β₁ expression in adults may require a conditional transgenic approach. Moreover, because the SM22α promoter drives transgene expression in the yolk sac vasculature at a time when embryonic survival is dependent on yolk sac function, use of the SM22α promoter to drive expression of 'vasculoactive' transgenes may be particularly likely to cause embryonic death.