Cardiac Lymphatics in Development and Repair

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Abstract With cardiovascular disease the leading cause of death worldwide, valvular heart disease (VHD) currently affects 2.5% of the US population and is one of the most important factors responsible for cardiovascular disease events. Even more surprising, a large-scale clinical study found previously undiagnosed VHD in 50% of the elderly population, further accentuating the need for a better understanding of the pathophysiology of VHDs. However, VHDs remain understudied, and the underlying pathological mechanisms are poorly characterized. Adrenomedullin (AM), a peptide hormone with numerous cardiovascular roles, has been recently shown as the most potent prognostic biomarker in aortic stenosis. Moreover, the AM decoy receptor, Atypical Chemokine Receptor 3 (ACKR3) also attenuates pro-fibrotic signaling and ACKR3-deficient mice display severe valvular defects, including thickened semilunar valves due to increased proliferation of the semilunar valve mesenchymal cells, and develop ventricular fibrosis. Nevertheless, the role of AM and its decoy receptor in cardiac valve development or function has yet not been investigated in detail. With this knowledge in mind, we hypothesize that endothelial and endocardial AM - ACKR3 signaling is a key player in regulating cardiac valvulogenesis and aberrant cardiac fibrosis. Using state-of-the-art light-sheet microscopy, single- cell RNA transcriptomic and animal model approaches, we propose to build on our current expertise GPCR signaling to broad our knowledge on how AM - ACKR3 signaling modulates cardiac health. Our studies will expand our understanding of the underlying molecular mechanisms leading to valvular defects and cardiac fibrosis formation and uncover possible molecular targets for patients with valvular heart diseases.