Abstract
Lymphangioleiomyomatosis (LAM) is a rare pulmonary disease characterised by the proliferation of smooth muscle-like cells (LAM cells), and an abundance of lymphatic vessels in LAM lesions. Studies reported that vascular endothelial growth factor-D (VEGF-D) secreted by LAM cells contributes to LAM-associated lymphangiogenesis, however, the precise mechanisms of lymphangiogenesis and characteristics of lymphatic endothelial cells (LECs) in LAM lesions have not yet been elucidated. In this study, human primary-cultured LECs were obtained both from LAM-affected lung tissues (LAM-LECs) and normal lung tissues (control LECs) using fluorescence-activated cell sorting (FACS). We found that LAM-LECs had significantly higher ability of proliferation and migration compared to control LECs. VEGF-D significantly promoted migration of LECs but not proliferation of LECs in vitro. cDNA microarray and FACS analysis revealed the expression of vascular endothelial growth factor receptor (VEGFR)-3 and integrin α9 were elevated in LAM-LECs. Inhibition of VEGFR-3 suppressed proliferation and migration of LECs, and blockade of integrin α9 reduced VEGF-D-induced migration of LECs. Our data uncovered the distinct features of LAM-associated LECs, increased proliferation and migration, which may be due to higher expression of VEGFR-3 and integrin α9. Furthermore, we also found VEGF-D/VEGFR-3 and VEGF-D/ integrin α9 signaling play an important role in LAM-associated lymphangiogenesis.
Highlights
Lymphangioleiomyomatosis (LAM) is a rare pulmonary disease characterised by the proliferation of smooth muscle-like cells (LAM cells), and an abundance of lymphatic vessels in LAM lesions
To ensure isolated CD31+/podoplanin + cells were lymphatic endothelial cells (LECs), we examined expression of the lymphatic-specific cell markers podoplanin, prospero homeobox protein 1 (PROX-1) and lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE-1) with immunocytochemistry and immunofluorescence staining
When LECs were co-stimulated with VEGF-A and either VEGF-C, -D or the combination of all 3 growth factors, we found no additive effect of either VEGF-C, -D, or both, on the degree of proliferation elevated by VEGF-A alone
Summary
Lymphangioleiomyomatosis (LAM) is a rare pulmonary disease characterised by the proliferation of smooth muscle-like cells (LAM cells), and an abundance of lymphatic vessels in LAM lesions. Studies reported that vascular endothelial growth factor-D (VEGF-D) secreted by LAM cells contributes to LAM-associated lymphangiogenesis, the precise mechanisms of lymphangiogenesis and characteristics of lymphatic endothelial cells (LECs) in LAM lesions have not yet been elucidated. LAM lesions in the lungs as well as retroperitoneal lymphangioleiomyomas, have abundant lymphatic vessels with irregularly dilated spaces or slit-like appearance together with proliferating LAM c ells[2,3] Corresponding with these pathological findings, LAM patients frequently develop lymphatic manifestations including chylous fluid accumulation in the pleural and/or peritoneal spaces, pulmonary lymphatic congestion, and lower extremity. This contributes to a better understanding of the pathobiology of LAM, a disease involving the lymphatic system
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