title: Experimental hypertension triggers varicosis-like maladaptive venous remodeling through activator protein-1.
abstract: An increase in circumferential wall tension (CWT) is an important determinant of vascular remodeling during hypertension or arteriosclerosis but also arteriogenesis. Although pivotal for such processes, the effect of this biomechanical force on venous remodeling has not yet been delineated. To this end, we raised the filling pressure in veins of the mouse auricle, which led to a 2.5-fold enlargement of these blood vessels within 4 d along with an increase in smooth muscle cell proliferation, matrix metalloproteinase 2 (MMP-2) expression and gelatinase activity. These changes were likewise observed in tissue samples of human varicose veins. Topical treatment of the auricles with a decoy oligonucleotide-neutralizing activator protein 1 (AP-1) inhibited these effects. Likewise, proliferation, MMP-2 expression, and gelatinase activity in both native and cultured venous smooth muscle cells exposed to enhanced stretch was decreased by up to 80% through inhibiting AP-1. In contrast, mutant control oligonucleotides had no effect on smooth muscle cell activation. These findings indicate that an increase in venous filling pressure and thus CWT is sufficient to activate AP-1, which, in turn, triggers varicose remodeling through fuelling MMP-2 activity and smooth muscle cell hyperplasia in the venous vessel wall.
authors.affiliation: University of Heidelberg, Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Feldner
authors.forename: Hannes
authors.initials: H
authors.lastname: Otto
authors.forename: Stephan
authors.initials: S
authors.lastname: Rewerk
authors.forename: Markus
authors.initials: M
authors.lastname: Hecker
authors.forename: Thomas
authors.initials: T
authors.lastname: Korff
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D054644:Ear Auricle / Q000098:blood supply; D018093:Gelatinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D006973:Hypertension; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011312:Pressure; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018808:Transcription Factor AP-1; D018093:Gelatinases; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse