Lasse Bach Steffensen1, Martin Bødtker Mortensen1, Mads Kjolby1, Mette Kallestrup Hagensen1, Claus Oxvig1, Jacob Fog Bentzon2. 1. From the Department of Cardiology, and Institute of Clinical Medicine, Aarhus University Hospital, Skejby, Denmark (L.B.S., M.B.M., M.K., M.K.H., J.F.B.); Department of Molecular Biology and Genetics (L.B.S., C.O.) and Department of Biomedicine (M.K.), Aarhus University, Aarhus, Denmark; and Department of Molecular Biology and Genetics (L.B.S., C.O.) and DANDRITE and Danish Diabetes Academy, Department of Biomedicine (M.K.), Aarhus University, Denmark. 2. From the Department of Cardiology, and Institute of Clinical Medicine, Aarhus University Hospital, Skejby, Denmark (L.B.S., M.B.M., M.K., M.K.H., J.F.B.); Department of Molecular Biology and Genetics (L.B.S., C.O.) and Department of Biomedicine (M.K.), Aarhus University, Aarhus, Denmark; and Department of Molecular Biology and Genetics (L.B.S., C.O.) and DANDRITE and Danish Diabetes Academy, Department of Biomedicine (M.K.), Aarhus University, Denmark. jben@clin.au.dk.
Abstract
OBJECTIVE: Atherosclerosis develops initially at branch points and in areas of high vessel curvature. Moreover, experiments in hypercholesterolemic mice have shown that the introduction of disturbed flow in straight, atherosclerosis-resistant arterial segments turns them highly atherosclerosis susceptible. Several biomechanical mechanisms have been proposed, but none has been demonstrated. In the present study, we examined whether a causal link exists between disturbed laminar flow and the ability of the arterial wall to retain lipoproteins. APPROACH AND RESULTS: Lipoprotein retention was detected at natural predilection sites of the murine thoracic aorta 18 hours after infusion of fluorescently labeled low-density lipoprotein. To test for causality between blood flow and the ability of these areas to retain lipoproteins, we manipulated blood flow in the straight segment of the common carotid artery using a constrictive collar. Disturbed laminar flow did not affect low-density lipoprotein influx, but increased the ability of the artery wall to bind low-density lipoprotein. Concordantly, disturbed laminar flow led to differential expression of genes associated with phenotypic modulation of vascular smooth muscle cells, increased expression of proteoglycan core proteins associated with lipoprotein retention, and of enzymes responsible for chondroitin sulfate glycosaminoglycan synthesis and sulfation. CONCLUSIONS: Blood flow regulates genes associated with vascular smooth muscle cell phenotypic modulation, as well as the expression and post-translational modification of lipoprotein-binding proteoglycan core proteins, and the introduction of disturbed laminar flow vastly augments the ability of a previously resistant, straight arterial segment to retain lipoproteins.
OBJECTIVE:Atherosclerosis develops initially at branch points and in areas of high vessel curvature. Moreover, experiments in hypercholesterolemicmice have shown that the introduction of disturbed flow in straight, atherosclerosis-resistant arterial segments turns them highly atherosclerosis susceptible. Several biomechanical mechanisms have been proposed, but none has been demonstrated. In the present study, we examined whether a causal link exists between disturbed laminar flow and the ability of the arterial wall to retain lipoproteins. APPROACH AND RESULTS: Lipoprotein retention was detected at natural predilection sites of the murine thoracic aorta 18 hours after infusion of fluorescently labeled low-density lipoprotein. To test for causality between blood flow and the ability of these areas to retain lipoproteins, we manipulated blood flow in the straight segment of the common carotid artery using a constrictive collar. Disturbed laminar flow did not affect low-density lipoprotein influx, but increased the ability of the artery wall to bind low-density lipoprotein. Concordantly, disturbed laminar flow led to differential expression of genes associated with phenotypic modulation of vascular smooth muscle cells, increased expression of proteoglycan core proteins associated with lipoprotein retention, and of enzymes responsible for chondroitin sulfate glycosaminoglycan synthesis and sulfation. CONCLUSIONS: Blood flow regulates genes associated with vascular smooth muscle cell phenotypic modulation, as well as the expression and post-translational modification of lipoprotein-binding proteoglycan core proteins, and the introduction of disturbed laminar flow vastly augments the ability of a previously resistant, straight arterial segment to retain lipoproteins.
Authors: Magda R Hamczyk; Ricardo Villa-Bellosta; Pilar Gonzalo; María J Andrés-Manzano; Paula Nogales; Jacob F Bentzon; Carlos López-Otín; Vicente Andrés Journal: Circulation Date: 2018-02-28 Impact factor: 29.690
Authors: Jan Borén; M John Chapman; Ronald M Krauss; Chris J Packard; Jacob F Bentzon; Christoph J Binder; Mat J Daemen; Linda L Demer; Robert A Hegele; Stephen J Nicholls; Børge G Nordestgaard; Gerald F Watts; Eric Bruckert; Sergio Fazio; Brian A Ference; Ian Graham; Jay D Horton; Ulf Landmesser; Ulrich Laufs; Luis Masana; Gerard Pasterkamp; Frederick J Raal; Kausik K Ray; Heribert Schunkert; Marja-Riitta Taskinen; Bart van de Sluis; Olov Wiklund; Lale Tokgozoglu; Alberico L Catapano; Henry N Ginsberg Journal: Eur Heart J Date: 2020-06-21 Impact factor: 29.983
Authors: Emily Keyes; Madison Grinnell; Douglas Jacoby; Thomas Vazquez; DeAnna Diaz; Victoria P Werth; Kevin Jon Williams Journal: Int J Womens Dermatol Date: 2021-09-09
Authors: Lucas Albacete-Albacete; Inmaculada Navarro-Lérida; Juan Antonio López; Inés Martín-Padura; Alma M Astudillo; Alessia Ferrarini; Michael Van-Der-Heyden; Jesús Balsinde; Gertraud Orend; Jesús Vázquez; Miguel Ángel Del Pozo Journal: J Cell Biol Date: 2020-11-02 Impact factor: 10.539