Genes and hypertension - From gene mapping in experimental models to vascular gene transfer strategies

Human essential hypertension is a complex, multifactorial, quantitative tra it under a polygenic control. Several strategies have been developed over t he last decade to dissect genetic determinants of hypertension. Of these, t he most successful have been studies that identified rare mendelian syndrom es in which a single gene mutation causes high blood pressure. The attempts to identify multiple gene, each with a small contribution to the common po lygenic form of hypertension, have been less successful. Several laboratori es focused their attention on rat models of genetic hypertension, which can be considered as a reductionist paradigm for human disease. Using numerous crosses between hypertensive and normotensive strains, investigators ident ified several quantitative trait loci (QTL) for blood pressure subphenotype s and for cardiovascular complications such as left ventricular hypertrophy , kidney failure, stroke, and insulin resistance. Furthermore, congenic str ains have been produced to confirm the existence of some of these QTL and t o narrow down the chromosomal regions of interest. A number of interesting strategies have been developed, including a "speed" congenic strategy perfe cted by our group in Glasgow. However, the limit of congenic strategy is es timated at 1 cM, which corresponds to 2 x 10(6) base pairs of DNA and appro ximate to 50 candidate genes. It is envisaged that gene expression profilin g with cDNA microarrays might allow a quick progression toward the gene ide ntification within cardiovascular QTL. In parallel experimental effort, sev eral laboratories have been developing gene transfer/therapy strategies wit h adenoviral or adeno-associated viral vectors used, for example, to overex press protective vascular genes such as vascular endothelial growth factor or endothelial nitric oxide synthase. It is anticipated that further develo pments in positional cloning of susceptibility and severity genes in hypert ension and its complications will lead to a direct transfer of these discov eries to essential hypertension in humans and will ultimately produce novel targets for local and systemic gene therapy in cardiovascular disease.