Dissecting the functional roles of cardiac lymphatics in ischemic heart disease

SUMMARY Myocardial infarction (MI) is a major cause of morbidity and mortality worldwide. Therefore, seeking new therapeutic approaches is still the priority in the field. Recent studies have shown that stimulation of lymphatic growth (lymphangiogenesis) after ischemic heart disease improves cardiac function and attenuates adverse cardiac remodeling, and cardiac lymphangiogenesis likely improves heart repair after injury by improving the clearance of inflammatory response. Furthermore, my published work has unraveled a novel additional mechanism that an “active”, pro-survival paracrine signaling (lymphoangiocrine, Reelin) from lymphatic endothelial cells promotes cardiomyocyte (CM) survival after injury, a result challenging the traditional view that lymphatics function as a “passive” route for fluid transport. However, the detailed mechanism/s by which increased lymphangiogenesis improves heart repair is not yet fully understood. Our exciting preliminary data suggest that lymphangiogenesis improves cardiac repair requires both, cardioprotective lymphoangiocrine signals and efficient lymphatic immune clearance function. This proposal is set out to use a various valuable animal models to determine these functional roles of cardiac lymphangiogenesis during cardiac repair. In the Aim 1 of the proposal, we will determine the molecular pathways and targets how cardiac lymphangiogenesis improve CM survival after MI. In the Aim 2 of this proposal, we aim to use a variety of lymphatic loss- and gain- of function mouse strains to characterize in details the lymphatic functions during cardiac repair, and determine the therapeutic potential of these optimal effects in treatment of ischemic disease. These fundamental findings will impact diverse fields including lymphatic biology and cardiovascular research, with an ultimate goal to identify novel targets for the treatment of cardiovascular diseases.