Endothelial plasticity: shaping health and disease

PhD ceremony: Mr. J.A.J. Moonen, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Endothelial plasticity: shaping health and disease

Promotor(s): prof. M.J.A. van Luyn

Faculty: Medical Sciences

It is well established that endothelial cells (EC) play a crucial role in vascular physiology. Originally regarded as a passive barrier, the endothelium has become appreciated as a complex tissue with multiple functions and critical for shaping health. This requires a high degree of adaptation and plasticity. Adverse stimuli such as pro-fibrotic and pro-inflammatory cytokines or reactive oxygen species, induce endothelial injury and dysfunction. When persistent, this dysfunction can result in endothelial-to-mesenchymal transition (EndMT) which contributes to fibro-proliferative disease. Hence, EC plasticity can also shape disease.

In this thesis we investigated how local environmental cues dictate endothelial plasticity. We have shown that chronic inflammatory disease impacts endothelial progenitor cell (EPC) biology, through reducing their circulating numbers and by impairing their function. Both mature EC and EPC were shown to be highly plastic in vitro, as evidenced by their capacities to undergo TGF-beta-driven EndMT. Also we have shown how biochemical stimuli, i.e., pro-fibrotic and pro-inflammatory cytokines, can act in synergy in induction of EndMT. And finally, how hemodynamic forces modulate EndMT both through inhibition, and stimulation of this process. Our findings provide insights in the regulation of EndMT in vivo, and its potential involvement in disease. Most importantly, our studies have shown that EC retain a remarkable plasticity during adult life. These insights open new horizons for vascular regenerative medicine and challenge current dogmas on the pathophysiology of fibro-proliferative vascular disease.