Introduction

The renin-angiotensin system (RAS) is a major regulator of vascular hemodynamics and a determinant of cardiovascular homeostasis. It also contributes to the development and maintenance of various forms of hypertension and other cardiovascular diseases such

From: Contemporary Cardiology: Cardiovascular Genomics Edited by: M. K. Raizada, et al. © Humana Press Inc., Totowa, NJ

as heart failure, cardiac hypertrophy, and atherosclerosis. Angiotensin II (ANG II), the primary effector of the RAS, is produced by the serial cleavage of angiotensinogen (AGT) by renin and angiotensin-converting enzyme (ACE). The actions of ANG II on distinct receptors (AT1a, AT1b, and AT2) located in vascular smooth muscle, kidney, adrenal gland, and brain lead to an elevation of arterial blood pressure through increased vascular resistance, cardiac output, sodium reabsorption and blood volume, and the production of other vasoactive hormones such as aldosterone (1,2). In addition, the RAS has been shown to play a role in regulating cell growth, in vascular smooth muscle proliferation, and during development (3,4). Based on the presence of different components of the RAS at both the protein and mRNA level in a variety of tissues, including adrenal gland, kidney, brain, heart, adipose tissue, and blood vessels, local-tissue RAS has been proposed (2,5,6).

We will describe here some of the genetic manipulations used to study the role of AGT in the control of blood pressure and cardiovascular-related functions. AGT has received particular attention for many reasons. First, AGT is the only known precursor of ANG II. Second, the strongest evidence implicating a gene as a cause of human essential hypertension is for the AGT gene, and association of AGT levels and hypertension has been reported in families (7,8). Third, transgenic animals expressing high levels of AGT have elevated blood pressure (9), whereas knockout mice lacking AGT have low blood pressure (10,11).

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