Abstract 512: Fibroblasts Associated with Cardiac Fibrosis Carry Endothelial Imprint: Implication for Endothelial to Mesenchymal Transition
Cardiac fibrosis is mediated by activated fibroblasts. The source for such fibroblasts is unknown and anti-fibrotic therapies are not available. Because the mesenchymal cells of the atrioventricular cushion emerge from endothelial origin during embryonic development, we hypothesized that a sub-population of adult fibroblasts could derive from endothelial cells via an endothelial-mesenchymal transition (EndMT). To test our hypothesis, we induced cardiac fibrosis by banding of the ascending aorta in two genetic mouse models to track the origins of fibroblasts in the heart. In Tie1Cre; R26stoplacZ mice, Cre recombinase is expressed in tie1 positive endothelial cells and mediates removal of a STOP cassette which flanks the lacZ gene, resulting in irreversible lacZ expression in endothelial cells. In FSP1-GFP transgenic mice, GFP is expressed under control of the fibroblast-specific FSP1 promoter. Using Tie1Cre; R26RstoplacZ as well as FSP1-GFP transgenic mice we demonstrate that cardiac fibrosis is associated with emergence of fibroblasts of endothelial cell origin, suggestive of EndMT. In fibrotic hearts about one sixth of fibroblasts (positive for FSP1) were also positive for LacZ, indicating that they are of endothelial origin. TGF-β1, a mediator of EndMT during embryonic cushion formation which is abundantly expressed in fibrotic hearts, induces adult coronary endothelial cells to undergo EndMT in vitro. EndMT associated with cardiac fibrosis was significantly inhibited in Smad3 heterozygous mice, in which TGF-β1 signalling is impaired, suggesting that EndMT involving adult cardiac endothelial cells is mediated by TGF-β1 in vivo and in vitro. Bone Morphogenic Protein 7 (BMP-7), a known antagonist of TGF-β1, preserves the endothelial phenotype and reverses EndMT in vitro. Systemic treatment with recombinant human BMP-7 (rhBMP-7) significantly inhibits EndMT and progression of cardiac fibrosis in a pressure overload and a chronic allograft rejection mouse model associated with functional improvement and reduced mortality. Our findings demonstrate that EndMT contributes to the progression of cardiac fibrosis. and that inhibition of EndMT by rhBMP-7 is a novel therapeutic approach to treat chronic heart disease associated with fibrosis.