Lymphatic vessels serve an essential function in maintaining interstitial fluid balance throughout the body. Functional disruption of lymphatic vessels by either surgery, radiation/chemotherapy or organ damage results in pathological lymphedema and subsequent interstitial fibrous deposition and inflammation. The heart contains a dense network of lymphatic vessels that exhibit coordinated flow with each contraction of the myocardium. Recent studies, including our own, have revealed a critical role for cardiac lymphatics in cardiac repair and maintenance of cardiac function following acute myocardial edema. Several groundbreaking studies have furthermore shown that cardiac lymphatics arise from at least 4 different progenitor cell populations, thereby illustrating their distinct and pleiotropic regulation during development and conditions of remodeling and repair. We have also discovered a significant increase in the number of cardiac lymphatics of female mice, compared to age-matched male mice, which could be the basis underlying some forms of cardioprotection in women. Therefore, the overall goal of this research proposal is to develop sophisticated cell based systems and genetic mouse model tools to address the function and modulation of cardiac lymphatic vessels in males and females and during different stages of development and repair. Based on our expertise in lymphatic vessel biology and our interest in the cardioprotective functions of adrenomedullin peptide, we feel that we are uniquely well-positioned to address several intriguing hypotheses. Results from our studies will provide conceptually novel insights into the largely unexplored role of cardiac lymphatic vessels in heart development, injury and sex-dependent cardioprotection.
The heart contains a dense network of lymphatic vessels that display coordinated outflow of excess tissue fluid with each contraction. When lymphatic function is compromised, tissues develop edema, which can lead to inflammation and fibrosis. However, it is not clear to what extent cardiac lymphatics, which differ between males and females, contribute to heart development and myocardial fluid balance. Studies proposed in this grant aim to address these questions by using sophisticated cell based and genetic mouse model systems.
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