ELEVATED BLOOD-PRESSURE AND ENHANCED MYOCARDIAL-CONTRACTILITY IN MICEWITH SEVERE IGF-1 DEFICIENCY

To circumvent the embryonic lethality of a complete deficiency in insu lin-like growth factor 1 (IGF-1), we generated mice homozygous for a s ite-specific insertional event that created a mutant IGF-1 allele (igf 1(m)). These mice have IGF-1 levels 30% of wild type yet survive to ad ulthood, thereby allowing physiological analysis of the phenotype. Min iaturized catheterization technology revealed elevated conscious blood pressure in IGF-1(m/m) mice, and measurements of left ventricular con tractility were increased. Adenylyl cyclase activity was enhanced in I GF-1(m/m) hearts, without an increase in beta-adrenergic receptor dens ity, suggesting that crosstalk between IGF-1 and beta-adrenergic signa ling pathways may mediate the increased contractility. The hypertrophi c response of the left ventricular myocardium in response to aortic co nstriction, however, was preserved in IGF-1(m/m) mice. We conclude tha t chronic alterations in IGF-1 levels can selectively modulate blood p ressure and left ventricular function, while not affecting adaptive my ocardial hypertrophy in vivo.