Lymphatic vessels serve an essential function in maintaining interstitial fluid balance throughout the body. They also serve as a conduit for the trafficking and maturation of immune cells. 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. However, whether lymphatic dysfunction contributes to the pathophysiological progression of heart injury following myocardial ischemia remains unknown. Furthermore, we lack a full understanding of the consequences of myocardial edema on heart function following ischemic heart disease. Therefore the overall goal of this research proposal is to develop sophisticated surgical and genetic mouse model tools to address the function and modulation of cardiac lymphatic vessels in heart disease. 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 the effects of either increased cardiac lymphatics or lymphatic insufficiency on the resolution or exacerbation of myocardial edema, respectively. Results from our studies will provide conceptually novel insights into the largely unexplored role of cardiac lymphatic vessels in myocardial edema.
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 and myocardial edema contribute to heart disease. Studies proposed in this grant aim to address this question by using sophisticated genetic and surgical mouse models with either deficits or activation of the lymphatic vascular system in heart disease.
|Mackie, Duncan I; Al Mutairi, Fuad; Davis, Reema B et al. (2018) hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia. J Exp Med 215:2339-2353|
|Quinn, K E; Mackie, D I; Caron, K M (2018) Emerging roles of atypical chemokine receptor 3 (ACKR3) in normal development and physiology. Cytokine 109:17-23|
|Xu, Wenjing; Wittchen, Erika S; Hoopes, Samantha L et al. (2018) Small GTPase Rap1A/B Is Required for Lymphatic Development and Adrenomedullin-Induced Stabilization of Lymphatic Endothelial Junctions. Arterioscler Thromb Vasc Biol 38:2410-2422|
|Pawlak, J B; Wetzel-Strong, S E; Dunn, M K et al. (2017) Cardiovascular effects of exogenous adrenomedullin and CGRP in Ramp and Calcrl deficient mice. Peptides 88:1-7|
|Kechele, Daniel O; Dunworth, William P; Trincot, Claire E et al. (2016) Endothelial Restoration of Receptor Activity-Modifying Protein 2 Is Sufficient to Rescue Lethality, but Survivors Develop Dilated Cardiomyopathy. Hypertension 68:667-77|
|Bosetti, Francesca; Galis, Zorina S; Bynoe, Margaret S et al. (2016) ""Small Blood Vessels: Big Health Problems?"": Scientific Recommendations of the National Institutes of Health Workshop. J Am Heart Assoc 5:|