title: Gene deletion of dopamine beta-hydroxylase and alpha1-adrenoceptors demonstrates involvement of catecholamines in vascular remodeling.
abstract: In vitro studies have shown that stimulation of alpha1-adrenoceptors (ARs) directly induces proliferation, hypertrophy, and migration of arterial smooth muscle cells and adventitial fibroblasts. In vivo studies confirmed these findings and showed that catecholamine trophic activity becomes excessive after experimental balloon injury and contributes to neointimal growth, adventitial thickening, and lumen loss. However, past studies have been limited by selectivity of pharmacological agents. The aim of this study, in which mice devoid of norepinephrine and epinephrine synthesis [dopamine beta-hydroxylase (DBH-/-)] or deficient in alpha1-AR subtypes expressed in murine carotid (alpha1B-AR-/- and alpha1D-AR-/-) were used, was to test the hypothesis that catecholamines contribute to wall hypertrophy after injury. At 3 wk after injury of wild-type mice, lumen area and carotid circumference increased significantly, and hypertrophy of media and adventitia was in excess of that needed to restore circumferential wall stress to normal. In DBH-/- and alpha1B-AR-/- mice, increases in lumen area, circumference, and hypertrophy of the media and adventitia were reduced by 50-91%, resulting in restoration of wall tension to nearly normal (DBH-/-) or normal (alpha1B-AR-/-). In contrast, in alpha1D-AR-/- mice, increases in lumen area, circumference, and wall hypertrophy were unaffected and wall thickening remained in excess of that required to return tension to normal. When examined 5 days after injury, proliferation and leukocyte infiltration were inhibited in DBH-/- mice. These studies suggest that the trophic effects of catecholamines are mediated primarily by alpha1B-ARs in mouse carotid and contribute to hypertrophic growth after vascular injury.
authors.affiliation: Dept. of Cell and Molecular Physiology, 6309 MBRB, Univ. of North Carolina, Chapel Hill, NC 27599-7545, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Susanna
authors.initials: S
authors.lastname: Cotecchia
authors.forename: Steven A
authors.initials: SA
authors.lastname: Thomas
authors.forename: Akito
authors.initials: A
authors.lastname: Tanoue
authors.forename: Gozoh
authors.initials: G
authors.lastname: Tsujimoto
authors.forename: James E
authors.initials: JE
authors.lastname: Faber
mesh_terms: D000818:Animals; D017209:Apoptosis; D002339:Carotid Arteries / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D020212:Carotid Artery Injuries / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D002395:Catecholamines / Q000378:metabolism*; D002455:Cell Division; D004299:Dopamine beta-Hydroxylase / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D007962:Leukocytes / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D002395:Catecholamines; D020033:Protein Isoforms; D018340:Receptors, Adrenergic, alpha-1; D004299:Dopamine beta-Hydroxylase