Angiogenic-regulatory network revealed by molecular profilingheart tissue following Akt1 induction in endothelial cells.

Akt is a pivotal signaling molecule involved in the regulation of angiogenesis. In order to further elucidate the role of Akt1 in blood vessel development, a tetracycline-regulated transgenic system was utilized to conditionally activate Akt1 signaling in endothelial cells to examine transcript expression changes associated with angiogenesis in the heart. Induction of Akt1 over the course of 6 weeks led to a 33% increase in capillary density without affecting overall heart growth. Transcript expression profiles in the hearts were analyzed with an Affymetrix GeneChip Mouse Expression Set 430 2.0, which represents approximately 45,000 cDNAs and ESTs. A total of 248 transcripts were differentially expressed between transgenic and control mice (fold change >/<1.8; false discovery rate < 0.1; P < 0.01). A subset of these differentially expressed transcripts included angiogenic growth factors, cytokines, and extracellular matrix proteins. More specifically, these transcripts included VEGF-receptor2, neuropilin-1, and connective tissue growth factor, each of which is implicated in blood vessel growth and the maintenance of vessel wall integrity. Furthermore, these factors may be involved in an autocrine-regulatory feedback system, one believed to promote vessel growth. Knowledge of these and other targets could be used to treat ischemic heart disease, a disease whose broad spectrum of manifestations range from patients with only effort-induced angina without myocardial damage, through stages of myocardial ischemia that are associated with reversible and irreversible impairment in left ventricular function, to states of irreversible myocardial injury and necrosis resulting in congestive heart failure (CHF).