title: Vascular endothelial growth factors C and D induces proliferation of lymphangioleiomyomatosis cells through autocrine crosstalk with endothelium.
abstract: Lymphangioleiomyomatosis (LAM) is a potentially fatal lung disease characterized by nodules of proliferative smooth muscle-like cells. The exact nature of these LAM cells and their proliferative stimuli are poorly characterized. Herein we report the novel findings that the lymphangiogenic vascular endothelial growth factors (VEGF) C and D induce LAM cell proliferation through activation of their cognate receptor VEGF-R3 and activation of the signaling intermediates Akt/mTOR/S6. Furthermore, we identify expression of the proteoglycan NG2, a marker of immature smooth muscle cells, as a characteristic of LAM cells both in vitro and in human lung tissue. VEGF-C-induced LAM cell proliferation was in part a result of autocrine stimulation that resulted from cross talk with lymphatic endothelial cells. Ultimately, these findings identify the lymphangiogenic VEGF proteins as pathogenic growth factors in LAM disease and at the same time provide a novel pharmacotherapeutic target for a lung disease that to date has no known effective treatment.
authors.affiliation: Thoracic Disease Research Unit, Division of Pulmonary, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Rachel B
authors.initials: RB
authors.lastname: Issaka
authors.forename: Saji
authors.initials: S
authors.lastname: Oommen
authors.forename: Shiv K
authors.initials: SK
authors.lastname: Gupta
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Myers
authors.forename: Jay H
authors.initials: JH
authors.lastname: Ryu
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Vlahakis
mesh_terms: D000941:Antigens / Q000378:metabolism; D019898:Autocrine Communication / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004727:Endothelium / Q000187:drug effects* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D018192:Lymphangioleiomyomatosis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000494:pharmacology*; D042643:Vascular Endothelial Growth Factor D / Q000494:pharmacology*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000941:Antigens; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D011509:Proteoglycans; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D040321:Vascular Endothelial Growth Factor Receptor-3; D000099216:Chondroitin Sulfate Proteoglycan 4; C546842:MTOR protein, human