title: An imbalance between VEGF and endostatin underlies impaired angiogenesis in gastric mucosa of aging rats.
abstract: Gastric mucosa of aging individuals exhibits increased susceptibility to injury and delayed healing. Our previous studies in young rats showed that healing of mucosal injury depends on and is critically dependent on VEGF and angiogenesis. Since angiogenesis in aging gastric mucosa has not been examined before, in this study we examined the extent to which angiogenesis is impaired in gastric mucosa of aging vs. young rats and determined the underlying mechanisms with a focus on mucosal expression of VEGF (proangiogenic factor) and endostatin (antiangiogenic factor). Aging rats had significantly impaired gastric angiogenesis by ~12-fold, 5-fold, 4-fold, and 3-fold, respectively (vs. young rats; all P < 0.001) at 24, 48, 72, and 120 h following ethanol-induced gastric injury and reduced and delayed healing of mucosal erosions. In gastric mucosa of aging (vs. young) rats at baseline, VEGF expression was significantly reduced, whereas endostatin levels were significantly increased (P < 0.05 and P < 0.01, respectively). In contrast to young rats, gastric mucosal VEGF levels did not increase following ethanol-induced injury in aging rats. MMP-9 enzyme activity was significantly higher in gastric mucosa of aging vs. young rats both at baseline (2.7-fold) and 24 h (3.8-fold) after ethanol injury (both P < 0.001). Since endostatin is generated from collagen XVIII by MMP-9, this finding can explain the mechanism of increased endostatin expression in aging gastric mucosa. The above findings demonstrate that reduced VEGF and increased endostatin result in the impaired angiogenesis and delayed injury healing in gastric mucosa of aging rats.
authors.affiliation: Veterans Affairs Long Beach Healthcare System, and Univ. of California, Irvine, 5901 E. 7th St., 09/151, Bldg. 162, Rm. 115, Long Beach, CA 90822. atarnawski@yahoo.com or andrzej.tarnawski@va.gov.
authors.forename: Amrita
authors.initials: A
authors.lastname: Ahluwalia
authors.forename: Michael K
authors.initials: MK
authors.lastname: Jones
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Deng
authors.forename: Zsusanna
authors.initials: Z
authors.lastname: Sandor
authors.forename: Sandor
authors.initials: S
authors.lastname: Szabo
authors.forename: Andrzej S
authors.initials: AS
authors.lastname: Tarnawski
mesh_terms: D000367:Age Factors; D000375:Aging / Q000378:metabolism*; D020751:Alcohol-Induced Disorders / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D043169:Endostatins / Q000378:metabolism*; D000431:Ethanol; D005753:Gastric Mucosa / Q000098:blood supply* / Q000293:injuries / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018919:Neovascularization, Physiologic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D062326:Re-Epithelialization; D013997:Time Factors; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D043169:Endostatins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D000431:Ethanol; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat
keywords: VEGF; aging; angiogenesis; endostatin; gastric mucosa; mucosal healing