Site-specific responses to monocrotaline-induced vascular injury: evidence for two distinct mechanisms of remodeling.
Monocrotaline (MCT)-induced pulmonary vascular injury was used to begin studying the mechanism(s) of vascular remodeling in Fischer 344 rats, using extracellular matrix (ECM) gene expression to define areas of remodeling. By day 28 after injection, pulmonary artery pressures were increased and right ventricular hypertrophy had developed compared with normal controls. Tropoelastin, fibronectin, and alpha 1(I) procollagen mRNA levels increased at least 2-fold by day 28. In situ hybridization demonstrated tropoelastin gene expression by cells adjacent to the lumen and procollagen gene expression at the medial-adventitial border in both small muscular and large elastic pulmonary arteries. This pattern of gene expression was observed as early as 1 wk after MCT injury. These observations indicated two distinct areas of remodeling, one along the vascular lumen at the site of monocrotaline-induced injury and the other at a second distinct site. To determine whether other differences may be involved at these two sites, the presence of transforming growth factor-beta (TGF-beta) was studied. Total TGF-beta protein was 4-fold higher in remodeling lungs compared with normal lungs. Gene expression for all three isoforms of TGF-beta colocalized with tropoelastin gene expression along the vascular lumen but not with alpha 1(I) procollagen gene expression. These results suggest a complex site-specific response to injury mediated by two distinct pathways in this model of pulmonary vascular remodeling.
Tanaka
Y
Y
Department of Medicine, Washington University Medical Center, St. Louis, Missouri, USA.
Bernstein
M L
ML
Mecham
R P
RP
Patterson
G A
GA
Cooper
J D
JD
Botney
M D
MD
D000818:Animals; D015152:Blotting, Northern; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D016326:Extracellular Matrix Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D006439:Hemodynamics / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000139:chemically induced*; D017403:In Situ Hybridization; D008168:Lung / Q000098:blood supply; D008297:Male; D016686:Monocrotaline; D011042:Poisons; D011347:Procollagen / Q000235:genetics; D011651:Pulmonary Artery / Q000166:cytology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013047:Specific Pathogen-Free Organisms; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014333:Tropoelastin / Q000235:genetics
D016326:Extracellular Matrix Proteins; D011042:Poisons; D011347:Procollagen; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014333:Tropoelastin; D016686:Monocrotaline