The lymphatic vasculature is a blind-ended network covering most tissues and organs of the body and is essential for vertebrate development and homeostasis. During pathological conditions lymphatic vessels expand via lymphangiogenesis to aid the clearance of interstitial fluid and reduce inflammation. Whilst the response of the lymphatics to injury and inflammation has been well documented at peripheral sites, there is minimal insight into their role(s) during pathophysiology of organ systems such as the heart. We investigated the response of the cardiac lymphatic vessels to myocardial infarction (MI) and observed a significant lymphangiogenic response, underpinned by reactivation of the developmental lymphatic programme. VEGF-C treatment significantly augmented lymphangiogenesis post-MI resulting in improved cardiac function. To determine whether this effect might be mediated by immunomodulation, we flow-sorted immune cells from VEGF-C treated hearts and observed increased clearance of macrophages to mediastinal lymph nodes by day 7 post-MI. The molecular phenotype of cleared versus retained macrophages was equivalent, suggesting that a reduction in macrophage load in the heart alone was sufficient to correlate with improved outcome. Finally, we examined macrophage trafficking in Lyve-1 knock-out mice, which have impaired immune cell uptake, and observed significantly reduced macrophage clearance, which correlated with reduced cardiac output, elevated fibrosis and increased pathological remodelling. These data suggest that invoking developmental lymphangiogenesis to modulate the innate immune response may represent a therapeutic target to promote optimal cardiac repair following injury.
Paul Riley is a Fellow of the Academy of Medical Sciences (elected 2014) and is the British Heart Foundation (BHF) Professor of Regenerative Medicine. He currently occupies the Chair of Development and Cell Biology in the Department of Physiology, Anatomy and Genetics at the University of Oxford. He is Director of the BHF Oxbridge Centre for Regenerative Medicine (from 2013; www.cardioscience.ox.ac.uk/bhf-centre-of-regenerative-medicine); co-founder of the Oxford spin-out OxStem Cardio (from 2016; www.oxstem.com/product-pipeline/cardio) and co-academic lead on the Oxford Medical Sciences Division’s Institute of Developmental and Regenerative Medicine (project completion 2021; www.bhf.org.uk/research-projects/funding-towards-a-new-oxford-institute-of-developmental-and-regenerative-medicine-idrm). He was formerly Professor of Molecular Cardiology at the UCL-Institute of Child Health, London, where he was a principal investigator within the Molecular Medicine Unit at UCL-ICH (1999-2011). Prior to this, he obtained his PhD at UCL (1992-1995) and completed post-doctoral fellowships at the Samuel Lunenfeld Research Institute, Toronto, Canada and the Weatherall Institute of Molecular Medicine, Oxford (1996-1999). In 2008, Professor Riley was awarded the Outstanding Achievement Award of the European Society of Cardiology (ESC) Council on Basic Sciences. Currently Professor Riley’s team is focusing on exploiting the full potential of activated resident epicardium-derived cells and coronary lymphatic endothelium towards regenerating the adult heart and understanding the mechanisms of activation of these distinct lineages to extrapolate to human patients suffering from cardiovascular disease.
For further information please visit: www.dpag.ox.ac.uk/research/riley-group-1