Unexpected maturation of PI3K and MAPK-ERK signaling in fetal ovine cardiomyocytes

Abstract

In the first two-thirds of gestation, ovine fetal cardiomyocytes undergo mitosis to increase cardiac mass and accommodate fetal growth. Thereafter, some myocytes continue to proliferate while others mature and terminally differentiate into binucleated cells. At term (145 days gestational age; dGA) about 60% of cardiomyocytes become binucleated and exit the cell cycle under hormonal control. Rising thyroid hormone (T3) levels near term (135 dGA) inhibit proliferation and stimulate maturation. However, the degree to which intracellular signaling patterns change with age in response to T3 is unknown. We hypothesized that in vitro activation of ERK, Akt, and p70(S6K) by two regulators of cardiomyocyte cell cycle activity, T3 and insulin like growth factor-1 (IGF-1), would be similar in cardiomyocytes at gestational ages 100 and 135 dGA. IGF-1 and T3 each independently stimulated phosphorylation of ERK, Akt, and p70(S6K) in cells at both ages. In the younger mononucleated myocytes, the phosphorylation of ERK and Akt was reduced in the presence of IGF-1 and T3. However, the same hormone combination led to a dramatic twofold increase in the phosphorylation of these signaling proteins in the 135 dGA cardiomyocytes-even in cells that were not proliferating. In the older cells, both mono- and binucleated cells were affected. In conclusion, fetal ovine cardiomyocytes undergo profound maturation-related changes in signaling in response to T3 and IGF-1, but not to either factor alone. Differences in age-related response are likely to be related to milestones in fetal cardiac development as the myocardium prepares for ex utero life.

Hypothyroidism in utero stimulates pancreatic beta cell proliferation and hyperinsulinaemia in the ovine fetus during late gestation

“…In fetal sheep, the prepartum surge in T 3 may promote a switch in pancreatic beta cell development from proliferation and growth to maturation, in a manner similar to that seen in cardiomyocytes near term (Chattergoon et al . , ). Beta cells in the ovine fetal pancreas become more responsive to glucose and amino acids with gestational age, especially over the perinatal period when circulating T 3 concentrations rise ((Philipps et al .…”

Electrical and mechanical stimulation of cardiac cells and tissue constructs

“…In addition, cardiac fibroblasts (CFs), are also affected by mechanical stimulation, demonstrating changes in migration [77], ECM expression [78], differentiation, and myofibroblast activation [79–83] following Rho/ROCK activation. MAPK and ERK activation can mediate hypertrophy [84–92], calcium handling [93], oxidative stress [94–97], remodeling [98], proliferation [99], apoptosis [100–105], and maturation in CMs [106–108]. CF response to oxidative stress [109] is also mediated by MAPK and ERK activation.…”

Endocrine and other physiologic modulators of perinatal cardiomyocyte endowment

“…IGF1 stimulates proliferation in cardiomyocytes cultured from both mid-gestation and near-term fetal sheep (Chattergoon et al 2014; Sundgren et al 2003), although whether it also causes cellular enlargement at term is debated (Sundgren et al 2003; Wang et al 2012). When chronically infused into the fetal circulation, IGF1 causes massive cardiac enlargement by stimulation of cellular proliferation without increased cellular enlargement or terminal differentiation (Sundgren et al 2003).…”