Cardiac growth and angiogenesis coordinated by intertissue interactions

Abstract

Cardiac hypertrophy and angiogenesis are coordinately regulated during physiological or adaptive cardiac growth, and disruption of the balanced growth and angiogenesis leads to contractile dysfunction and heart failure. Coordination of growth and angiogenesis is in part mediated by the secretion of angiogenic growth factors from myocytes in response to hypertrophic stimuli, which enables the vasculature to "catch up" to the growth of the myocardium. In this issue of the JCI, two studies provide novel insights into the regulatory mechanisms of cardiac growth and coronary angiogenesis. Heineke et al. demonstrate that GATA4 acts as a stress-responsive transcription factor in murine cardiac myocytes that induces the expression of angiogenic growth factors (see the related article beginning on page 3198). Tirziu et al. show that enhanced coronary angiogenesis per se leads to hypertrophic growth of myocytes through a nitric oxide-dependent mechanism (see the related article beginning on page 3188). These studies, together with previous reports, suggest the existence of reciprocal signals between the myocardium and the vasculature that promote the growth of each other in a paracrine fashion.

Figure 1. Reciprocal signals between the myocardium and the vasculature coordinately regulate cardiac growth and coronary angiogenesis.

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.