title: An important role of matrix metalloproteinase-8 in angiogenesis in vitro and in vivo.
abstract: OBJECTIVE
  Growing evidence suggests a close association of plaque angiogenesis with atherosclerotic plaque formation and progression, and an important role of matrix metalloproteinase (MMP) in angiogenesis and atherosclerosis. We attempted to investigate the functional involvements of MMP8 in angiogenesis.
  
  
  RESULTS
  Knockdown of MMP8 in human umbilical vein endothelial cells (HuVECs) with MMP-8 shRNA lentivirus resulted in a decrease in in vitro capillary-like network formation, cell proliferation and migration, and impaired its capacity of in vivo angiogenesis. Less nuclear accumulation of β-catenin and lower β-catenin target gene expression levels was observed in the HuVECs expressing lower levels of endogenous MMP8. Knockdown of endogenous MMP8 in HuVECs down-regulated platelet/endothelial cell adhesion molecule-1 (PECAM-1) expression by converting less angiotensin I to II, which is an inducer for PECAM-1 gene expression. Aortic rings isolated from MMP8(-/-)/apoE(-/-) mice had less endothelial cell sprouting, and endothelial cells in MMP8(-/-)/apoE(-/-) mice had a lower ability to migrate into Matrigel plugs and less capacity of proliferation and angiogenesis. Moreover, immunohistochemical analyses revealed that MMP8 was expressed in microvessels within human atherosclerotic plaques and aneurysm. Finally, analyses of MMP8(-/-)/apoE(-/-) and MMP8(+/+)/apoE(-/-) mice fed a Western diet for 12 weeks showed that MMP8-deficient mice had small lesion size and less endothelial cells within atherosclerotic lesions.
  
  
  CONCLUSIONS
  We demonstrated for the first time that MMP8 plays an important role in angiogenesis in vitro and in vivo. Our findings provide new insights into the molecular mechanisms of plaque angiogenesis and suggest that MMP8 is a potential therapeutic target of cardiovascular diseases.
authors.affiliation: Department of Cardiovascular Surgery, Qilu Hospital, School of Medicine, Shandong University, Jinan, China.
authors.forename: Changcun
authors.initials: C
authors.lastname: Fang
authors.forename: Guanmei
authors.initials: G
authors.lastname: Wen
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Luyang
authors.initials: L
authors.lastname: Lin
authors.forename: Andrew
authors.initials: A
authors.lastname: Moore
authors.forename: Shuming
authors.initials: S
authors.lastname: Wu
authors.forename: Shu
authors.initials: S
authors.lastname: Ye
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Xiao
mesh_terms: D000783:Aneurysm / Q000201:enzymology / Q000473:pathology; D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology*; D006801:Humans; D020784:Matrix Metalloproteinase 8 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D058226:Plaque, Atherosclerotic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D051176:beta Catenin / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; C495270:CTNNB1 protein, human; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D051176:beta Catenin; D000804:Angiotensin II; D000803:Angiotensin I; C488762:MMP8 protein, human; C576328:MMP8 protein, mouse; D020784:Matrix Metalloproteinase 8
keywords: Angiogenesis; Atherosclerosis; Matrix metalloproteinase-8; Migration; Platelet endothelial cell adhesion molecule-1; Proliferation; β-catenin