Cardiovascular overexpression of transforming growth factor-beta(1) causes abnormal 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 increased vascular TGF-beta(1) expression remain controversial. To establish an experimental setting for investigating the role of increased TGF-beta(1) in vascular development and disease, we generated transgenic mice in which a cDNA encoding a constitutively active form of TGF-beta(1) is expressed from the SM22alpha 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 SM22alpha-directed transgene expression (heart, somites, and vasculature of the embryo and yolk sac) in embryos carrying an SM22alpha-beta-galactosidase transgene. SM22alpha- beta-galactosidase transgenic mice were born at the expected frequency (13%); however, nearly all SM22alpha-TGF-beta(1) transgenic mice died before E11.5. SM22alpha-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 SM22alpha promoter is lethal at E8.5 to E10.5, most likely because of yolk sac insufficiency. Investigation of the consequences of increased vascular TGF-beta(1) expression in adults may require a conditional transgenic approach. Moreover, because the SM22alpha promoter drives transgene expression in the yolk sac vasculature at a time when embryonic survival is dependent on yolk sac function, use of the SM22alpha promoter to drive expression of "vasculoactive" transgenes may be particularly likely to cause embryonic death.
Agah
R
R
Gladstone Institute of Cardiovascular Disease, San Francisco, Calif, USA.
Prasad
K S
KS
Linnemann
R
R
Firpo
M T
MT
Quertermous
T
T
Dichek
D A
DA
D000818:Animals; D001808:Blood Vessels / Q000196:embryology; D002319:Cardiovascular System / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000502:physiology; D005313:Fetal Death / Q000209:etiology*; D005327:Fetal Resorption / Q000209:etiology; D015870:Gene Expression / Q000235:genetics; D006321:Heart / Q000196:embryology; D006412:Hematopoietic Stem Cells / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D008840:Microfilament Proteins / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics; D015017:Yolk Sac / Q000098:blood supply* / Q000166:cytology
D008840:Microfilament Proteins; D009124:Muscle Proteins; C058992:Tagln protein, mouse; D016212:Transforming Growth Factor beta; C051615:transgelin