The Insulin-like Growth Factor Signalling Pathway in Cardiac Development and Regeneration

Abstract

Insulin and Insulin-like growth factors (IGFs) perform key roles during embryonic development, regulating processes of cell proliferation and survival. The IGF signalling pathway comprises two IGFs (IGF1, IGF2), two IGF receptors (IGFR1, IGFR2), and six IGF binding proteins (IGFBPs) that regulate IGF transport and availability. The IGF signalling pathway is essential for cardiac development. IGF2 is the primary mitogen inducing ventricular cardiomyocyte proliferation and morphogenesis of the compact myocardial wall. Conditional deletion of the Igf1r and the insulin receptor (Insr) genes in the myocardium results in decreased cardiomyocyte proliferation and ventricular wall hypoplasia. The significance of the IGF signalling pathway during embryonic development has led to consider it as a candidate for adult cardiac repair and regeneration. In fact, paracrine IGF2 plays a key role in the transient regenerative ability of the newborn mouse heart. We aimed to review the current knowledge about the role played by the IGF signalling pathway during cardiac development and also the clinical potential of recapitulating this developmental axis in regeneration of the adult heart.

Keywords: heart development; insulin-like growth factor receptors; insulin-like growth factors; myocardial proliferation.

Figure 1

Main functions of the IGF signalling system in cardiac development and in the heart of neonate mice. Both cardiomyocyte proliferation and postnatal cardiac growth are regulated by this system, where IGF1 and IGF2 play different roles.

Figure 2

The insulin growth factor signalling pathway in myocardial development. The relative importance of IGFR1 and INSR in the transduction of the mitogenic IGF2 signal has been debated, but IGF1R seems to be the main receptor in the embryonic cardiomyocytes. IGFBPs modulate bioavailability of IGF2. IGF2R is a negative regulator of the system by receptor-mediated endocytosis of IGF2. The main transduction pathways activated by IGF1R are the ERK/MAPK and the PI3K/Akt cascades, leading to proliferation and survival of the cardiomyocytes.