title: Opposing effects of bim and bcl-2 on lung endothelial cell migration.
abstract: Integration of cell adhesive, survival, and proliferative processes is essential for capillary morphogenesis of endothelial cells (EC) in vitro and vascular development and function in vivo. Unfortunately, the molecular and cellular mechanisms that impact these processes are poorly defined. Here we examined how lack of bim and/or bcl-2 expression impact lung EC function. The absence of bcl-2 or bim had a significant impact on EC adhesion and migration. Lack of bcl-2 expression decreased lung EC migration, whereas lack of bim expression increased migration compared with their wild-type counterparts. Decreased adhesion to fibronectin and vitronectin was observed in both bcl-2-/- and bim-/- lung EC, with bcl-2-/- EC having very little adhesion to either matrix protein. Capillary morphogenesis was greatly diminished in bcl-2-/- EC, which correlated with decreased lung alveolarization in vivo, an angiogenesis-dependent process. We also observed aberrant production of extracellular matrix proteins, eNOS expression, and nitric oxide production in bcl-2-/- lung EC, which could contribute to inability to undergo capillary morphogenesis. The changes in cell adhesion and migration noted in the absence of bim or bcl-2 were independent of their impact on apoptosis. We observed no significant affect on the steady-state rate of apoptosis of lung EC in the absence of bim or bcl-2. Thus, bcl-2 family members, bim and bcl-2, play a central role in modulation of EC proangiogenic properties, which goes beyond their role as simple mediators of mitochondrial homeostasis and apoptosis.
authors.affiliation: Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792-4108, USA.
authors.forename: Cathy
authors.initials: C
authors.lastname: Grutzmacher
authors.forename: SunYoung
authors.initials: S
authors.lastname: Park
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Elmergreen
authors.forename: Yixin
authors.initials: Y
authors.lastname: Tang
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Scheef
authors.forename: Nader
authors.initials: N
authors.lastname: Sheibani
authors.forename: Christine M
authors.initials: CM
authors.lastname: Sorenson
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000378:metabolism; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005472:Fluorouracil / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D008168:Lung / Q000166:cytology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000963:Antimetabolites; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D015815:Cell Adhesion Molecules; D016326:Extracellular Matrix Proteins; D016023:Integrins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D052250:Nitric Oxide Synthase Type III; D005472:Fluorouracil