Cardiac lymphatics are critical for basal heart function through the maintenance of interstitial fluid homeostasis and trafficking of immune cells. Importantly, there is a significant lymphangiogenic response following myocardial infarction (MI) in mice, and therapeutic targeting of cardiac lymphatics with a lymphangiogenic factor VEGF-C following MI in rodents can improve heart function, reduce myocardial edema, and reduce fibrosis. Myocardial edema, where excess interstitial fluid accumulates within the myocardium, is caused by disturbances in microvascular dynamics and the inability of cardiac lymphatics to respond to these changes. Myocardial edema can result from a multitude of cardiac insults, both acute and chronic, including MI, hypertension, cardioplegic arrest, and heart failure, and myocardial edema itself can cause a decrease in cardiac output and an increase in fibrosis. However, there is a paucity of knowledge in how cardiac lymphatics respond to non-infarct injuries that produce myocardial edema, making it critical to study myocardial edema due to its significance and potential therapeutic benefit in human disease. My preliminary data shows we can induce myocardial edema in mice through cauterization of the coronary sinus, which we can measure with both gravimetric analysis and histology. Importantly, we have preliminary data showing a lymphangiogenic response to an acute myocardial edema challenge. Thus, in Aim 1, I will establish a detailed model of myocardial edema in mice to measure the induction and resolution of myocardial edema, and the consequences on cardiac lymphatics and heart function. Incredibly, the field of cardiac lymphatics has not explored if there is a sex related difference in the response of cardiac lymphatics to any injury. Thus, I will compare how female and male mice respond to myocardial edema. Preliminary data suggests female mice resolve myocardial edema faster than males, and we will confirm this phenotype by ovariectomizing female mice with the hypothesis that they respond similarly to male mice. Transcriptional changes are also known to occur in lymphatic endothelial cells (LECs) in response to mechanotransduction, and so we will perform RNA-sequencing on mice that have induced myocardial edema with mice that have not, and expect to see transcriptional changes. To further characterize the role of cardiac lymphatics in myocardial edema resolution, in Aim 2 I will explore how a lymphatic insufficient genetic mouse model will respond to myocardial edema. I hypothesize that they will not be able to properly resolve the injury and have worse fibrosis and cardiac output than controls. Results from these experiments will expand our understanding of the function of cardiac lymphatics in both males and females during myocardial injury, and open up the possibility of testing therapies in this model.
Heart disease is the leading cause of death in the United States, and the number of people diagnosed with heart failure is predicted to rise 46% by 2030. Heart disease causes myocardial edema, which can decrease cardiac output and increase cardiac fibrosis. Completion of this proposal will advance our understanding of cardiac lymphatics, which can be therapeutically targeted to resolve myocardial edema and ultimately improve outcome in patients with heart disease.
