In the myocardium (left), hypertrophic stimuli activate multiple protein kinases such as Akt, ERK, and p38, which upregulate the transcriptional activity of GATA4 either directly or indirectly. At the same time, tissue hypoxia induced by cardiac growth, or activation of the Akt-mTOR pathway, stabilizes HIF-1. Activation GATA4 and HIF-1 in the nucleus leads to the expression of angiogenic growth factor genes, which act on the vasculature (right) to induce angiogenesis. The vasculature, on the other hand, when stimulated with angiogenic growth factors, secrets unidentified growth factor(s), which act on the myocardium to promote hypertrophy. Thus coordinated hypertrophy and angiogenesis is mediated by reciprocal signals between the myocardium and the vasculature in a paracrine fashion.