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Transgenic Animals as Tools in Hypertension Research

Gene transfer technology was developed in murine embryos over 15 years ago, and since then, several thousand reports using transgenic animals have been published. A transgenic animal is defined as containing a segment of exogenous genetic material stably incorporated into the genome, which results in a new trait that can be transmitted to successive generations. These animals have been used as models to investigate basic mechanisms of gene regulation, to study mammalian development, and to construct models that emulate human diseases such as cancer, AIDS, Alzheimer's, and cardiovascular disease. The development of this technology affords an unprecedented opportunity for investigators to examine the pathogenesis, progression, and treatment of genetic diseases and disorders. With the use of recombinant DNA techniques, the expression of normal genes or their disease counterparts can be targeted to nearly any tissue, their regulation can be studied mechanistically or perturbed, and the pathophysiological consequences of these manipulations considered. In this review, the methodology required to generate transgenic animals and an assessment of how these tools have been used to forward research into our understanding of hypertension, a major risk factor associated with cardiovascular disease, will be discussed. At the heart of generating transgenic animals is the methodology to manipulate the animals' genome during the earliest embryological stage. Three main methods to accomplish this are currently in use: (i) micro-injection of 1-cell fertilized embryos, (ii) retroviral mediated transduction, and (iii) genetic manipulation of embryonic stem cells. Although the technology now exists to generate transgenic rats, sheep, pigs, and other agriculturally important species (1-8), nearly all of the reports published thus far have utilized mice. A number of factors have made mice the overwhelming choice for transgenic studies. First and foremost, mice have a long history as tools for classical genetics, a result of which is the availability of a wide range of mutant stocks, a large number of highly inbred strains, genetically distinct wild derived species, congenic strains, and a number of recombinant inbred sets. A large linkage map of all mouse chromosomes has been determined, and a host of tools are available to quickly map the location of new traits (reviewed in 9). Additionally, although the initial setup associated with a transgenic lab can be quite expensive ($50,000-$120,000), this does not begin to compare to the staggering, and ever increasing cost of purchasing mice and maintaining breeding colonies. Consequently, economic factors have played and continue to play an unfortunate role in making the mouse the most utilized animal thus far. This has far reaching ramifications since larger animals have classically been used for cardiovascular research, and much recent effort has been directed at generating larger transgenic animals. These issues notwithstanding, the mouse is clearly the easiest mammalian species to manipulate at the genetic level. Therefore, all of the technical aspects discussed below pertain to routine practices performed in mice.