Developmental biologyP476Physiological role of FGF signaling in embryonic cardiac wall growth and adaptation to pressure overload

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Abstract

Fibroblast growth factors (FGFs) and their receptors play an important role during embryonic induction and patterning, as well as in modulating proliferative and hypertrophic growth in fetal and adult organs. Exogenous FGF2 (also known as basic FGF) was found to be able to induce proliferation of chick embryonic and fetal cardiac myocytes in vivo and is also important for vascular development.

The aim of this study was to assess the effect of FGF2 signaling on growth of chick embryonic ventricular wall and its vascularization.

Methods

In the first set of experiments, left ventricular wall of E7 chick embryos was injected with either GFP-expressing replication-deficient adenovirus alone or in combination with adenoviral vector encoding human FGF-2 gene. In the second set of experiments, FGF signaling was blocked in E8 chick embryos using FGF receptor tyrosine kinase inhibitor SU 5402. Hearts were sampled at ED9 for both protocols. In the third set of experiments we tested whether FGF2 signaling is involved in transmission of mechanical stretch to myocyte growth in vivo using an established pressure overload model.

Results

(1) Morphological examination of adenovirus-injected hearts revealed no difference in normal myocardial architecture, but increased levels of myocyte proliferation in hearts injected with FGF-2 adenovirus. There was no difference in capillary density or coronary artery anomalies.

Results

(2) Blocking of FGF signaling with SU 5402 led to hemorrhages in the areas of developing vasculature in epicardium. However, rates of myocyte proliferation were unchanged.

Results

(3) In pressure-overloaded hearts proliferation was increased significantly at the 48h sampling interval. Neither Western blot, nor immunohistochemistry performed on paraffin sections revealed any changes in the amount of myocardial FGF2. However, ELISA showed a significant increase of FGF2 in the serum. Increased amount of FGF2 mRNA in heart extracts was confirmed by RT PCR.

Results

We conclude that up-regulation of FGF2 signaling has a positive effect on growth of the embryonic heart, while its inhibition impacts mainly vasculogenesis, pointing to partial functional redundancy in paracrine control of cell proliferation in the developing heart.

Results

FGF2 synthesis is induced in embryonic ventricular cardiomyocytes in response to increased stretch due to pressure overload. However, increased stretch causes its release into serum, causing it to act in endocrine, rather then the usual paracrine manner.

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