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(Circulation Research. 2000;86:1024.)
© 2000 American Heart Association, Inc.

Molecular Medicine

Cardiovascular Overexpression of Transforming Growth Factor-ß₁ Causes Abnormal Yolk Sac Vasculogenesis and Early Embryonic Death

Ramtin Agah, K. S. Srinivasa Prasad, Ruth Linnemann, Meri T. Firpo, Thomas Quertermous, David A. Dichek

From the Gladstone Institute of Cardiovascular Disease, San Francisco, Calif (R.A., R.L., D.A.D.); the Departments of Medicine (R.A., D.A.D.) and Obstetrics, Gynecology, and Reproductive Sciences (M.T.F.) and the Cardiovascular Research Institute (R.A., D.A.D.), University of California, San Francisco; and the Department of Medicine, Stanford University, Stanford, Calif (K.S.S.P., T.Q.).

Correspondence to David A. Dichek, MD, Gladstone Institute of Cardiovascular Disease, PO Box 419100, San Francisco, CA 94141-9100. E-mail ddichek{at}gladstone.ucsf.edu

Abstract—Transforming growth factor-ß₁ (TGF-ß₁) is expressed in the adult and embryonic vasculature; however, the biological consequences of increased vascular TGF-ß₁ expression remain controversial. To establish an experimental setting for investigating the role of increased TGF-ß₁ in vascular development and disease, we generated transgenic mice in which a cDNA encoding a constitutively active form of TGF-ß₁ is expressed from the SM22 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-directed transgene expression (heart, somites, and vasculature of the embryo and yolk sac) in embryos carrying an SM22–ß-galactosidase transgene. SM22– ß-galactosidase transgenic mice were born at the expected frequency (13%); however, nearly all SM22–TGF-ß₁ transgenic mice died before E11.5. SM22–TGF-ß₁ 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-ß₁ from the SM22 promoter is lethal at E8.5 to E10.5, most likely because of yolk sac insufficiency. Investigation of the consequences of increased vascular TGF-ß₁ expression in adults may require a conditional transgenic approach. Moreover, because the SM22 promoter drives transgene expression in the yolk sac vasculature at a time when embryonic survival is dependent on yolk sac function, use of the SM22 promoter to drive expression of "vasculoactive" transgenes may be particularly likely to cause embryonic death.

Key Words: blood vessels • transgenic mice • morphogenesis • hematopoiesis

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