Abstract 16926: Phenotypically Heterogeneous Podoplanin-expressing Populations are Associated With Lymphatic Vessel Growth and Fibrogenic Responses in the Acutely and Chronically Infarcted Myocardium
Introduction: The cardiac lymphatic system is crucial for the control of intra-myocardial pressure and prevention of edema, lipid metabolism, and balanced regulation of tissue inflammation. Cardiac lymphatic vasculature undergoes substantial expansion in response to myocardial infarction (MI). Yet, there is limited information on the cellular mechanisms mediating post-MI lymphangiogenesis and accompanying fibrosis in the adult heart.
Methods and Results: We examined spatiotemporal changes in the expression of lymphatic endothelial determinants and mesenchymal markers in acutely and chronically infarcted mouse hearts subjected to permanent coronary artery ligation. We found that relative to sham-operated controls, a more than 3-fold increase in the frequency of cells exhibiting a lymphatic endothelial marker, podoplanin, occurred at 2 days after MI. Surprisingly, along with the LYVE-1-positive lymphatic vessels, podoplanin immunoreactivity detected masses of LYVE-1-negative cells dispersed between surviving myocytes in vicinity of the infarcted region, and to a lesser extent, remote area. The podoplanin-bearing population ubiquitously displayed a mesenchymal progenitor marker PDGFRα but not PDGFRβ, and intermittently expressed Prox-1, a master regulator of the lymphatic endothelial fate. At the stages of scar formation and maturation, 2 weeks and 1 month after MI, concomitantly with the enlargement of lymphatic network in the injured myocardium, the podoplanin-rich LYVE-1-negative multicellular assemblies that acquired PDGFRβ expression were apparent in the fibrotic area, aligned with extracellular matrix deposits, or located in immediate proximity to activated blood vessels. Although podoplanin and Prox-1 were highly represented in the area affected by MI, the podoplanin-containing cells were not consistently Prox-1-positive. The concordance of podoplanin with VEGFR-3 similarly varied.
Conclusions: Our data reveal previously unknown phenotypic and structural heterogeneity within the podoplanin-positive cell compartment in the infarcted heart, and suggest an alternate ability of podoplanin-presenting cardiac cells to generate lymphatic endothelium and pro-fibrotic cells, contributing to scar development.
Author Disclosures: M. Cimini: None. A. Cannata: None. C.A. MacRae: None. M. Rota: None. P. Goichberg: None.
- © 2016 by American Heart Association, Inc.