PRIMA · Predicting the Regeneration of an Infarct by leveraging the Mechanobiology of Angiogenesis

Acute myocardial infarction (AMI) is a significant global health issue. Current therapies cannot regenerate the hearts of survivors, leading to frequent AMI recurrence and premature death. Crucially, these therapies fail to induce sufficient blood vessel formation, i.e. angiogenesis, which is essential to regenerate the cardiac microvasculature. Without this vasculature, cells repopulating the infarcted tissue cannot survive. A deeper understanding and better control of post-AMI angiogenesis would thus transform patient outcomes. Cells in the infarcted heart experience complex, time-evolving mechanical environments. Despite the proven role of mechanical stimuli in regulating angiogenesis in other tissues, the impact of evolving cardiac mechanical cues on post-AMI angiogenesis is unclear. With PRIMA, I aim to mechanistically understand how these evolving cues affect post-AMI angiogenesis and how to leverage this new understanding to regenerate the microvasculature. I will achieve this aim by developing a revolutionary framework featuring in vitro and in silico models of cardiac angiogenesis. These models will address the evolving mechanical cues of the infarcted heart and the cell memory of past mechanical cues (mechanical memory). The new in vitro models will expose cells to mechanical cues mimicking the cardiac tissue. The resulting insights will inform multiscale computational models to predict angiogenesis and its subcellular mechanisms in response to macroscale changes in cardiac mechanical cues. The multiscale simulations, validated by in vitro models, will finally translate the in vitro findings to the complex in vivo setting and will identify new strategies to restore the microvasculature post-AMI.Building on this unique idea and multidisciplinary approach, PRIMA will have a ground-breaking impact on cardiac interventions, by revealing mechanical cues and cell mechanoresponsive mechanisms as new targets to maximize cardiac revascularization and function.