Cardiovascular Overexpression of Transforming Growth Factor-β1 Causes Abnormal Yolk Sac Vasculogenesis and Early Embryonic Death

• Published in: Circulation research Vol. 86; no. 10; pp. 1024 - 1030
• Main Authors: Agah, Ramtin, Prasad, K S. Srinivasa, Linnemann, Ruth, Firpo, Meri T, Quertermous, Thomas, Dichek, David A
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 26-05-2000; Lippincott
• Subjects: Biological and medical sciences; Blood vessels and receptors; Fundamental and applied biological sciences. Psychology; Vertebrates: cardiovascular system; Embryo; Mortality; Rodentia; Transgenic animal; Gene overexpression; Artery; Myocyte; Angiogenesis; Yolk sac; Vertebrata; Mammalia; Mouse; Hematopoiesis; Blood vessel; Circulatory system; Transforming growth factor β1
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.86.10.1024

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.