AimsPathological tissue remodelling by myofibroblast contraction is a hallmark of cardiac fibrosis. Myofibroblasts differentiate from cardiac fibroblasts under the action of transforming growth factor-b1 (TGF-b1), which is secreted into the extracellular matrix as a large latent complex. Integrin-mediated traction forces activate TGF-b1 by inducing a conformational change in the latent complex. The mesenchymal integrins avb5 and avb3 are expressed in the heart, but their role in the activation of TGF-b1 remains elusive. Here, we test whether targeting avb5 and avb3 integrins reduces latent TGF-b1 activation by cardiac fibroblasts with the goal to prevent the formation of a-smooth muscle actin (a-SMA)-expressing cardiac myofibroblasts and their contribution to fibrosis. Methods and resultsUsing a porcine model of induced right ventricular fibrosis and pro-fibrotic culture conditions, we show that integrins avb5 and avb3 are up-regulated in myofibroblast-enriched fibrotic lesions and differentiated cultured human cardiac myofibroblasts. Both integrins autonomously contribute to latent TGF-b1 activation and myofibroblast differentiation, as demonstrated by function-blocking peptides and antibodies. Acute blocking of both integrins leads to significantly reduced TGF-b1 activation by cardiac fibroblast contraction and loss of a-SMA expression, which is restored by adding active TGF-b1. Manipulating integrin protein levels in overexpression and shRNA experiments reveals that both integrins can compensate for each other with respect to TGF-b1 activation and induction of a-SMA expression. ConclusionsIntegrins avb5 and avb3 both control myofibroblast differentiation by activating latent TGF-b1. Pharmacological targeting of mesenchymal integrins is a possible strategy to selectively block TGF-b1 activation by cardiac myofibroblasts and progression of fibrosis in the heart.--

These data can serve as the basis for comparison with pathologic feet for both diagnostic and therapeutic purposes.

Neonatal pulmonary vein banding in piglets recapitulates critical aspects of clinical PVS and highlights a pathologic profile consistent with EndMT, supporting the rationale for evaluating therapeutic strategies designed to exploit reversibility of upstream pulmonary vein pathology.