title: Heart rate-associated mechanical stress impairs carotid but not cerebral artery compliance in dyslipidemic atherosclerotic mice.
abstract: The cardiac cycle imposes a mechanical stress that dilates elastic carotid arteries, while shear stress largely contributes to the endothelium-dependent dilation of downstream cerebral arteries. In the presence of dyslipidemia, carotid arteries stiffen while the endothelial function declines. We reasoned that stiffening of carotid arteries would be prevented by reducing resting heart rate (HR), while improving the endothelial function would regulate cerebral artery compliance and function. Thus we treated or not 3-mo-old male atherosclerotic mice (ATX; LDLr(-/-):hApoB(+/+)) for 3 mo with the sinoatrial pacemaker current inhibitor ivabradine (IVA), the β-blocker metoprolol (METO), or subjected mice to voluntary physical training (PT). Arterial (carotid and cerebral artery) compliance and endothelium-dependent flow-mediated cerebral dilation were measured in isolated pressurized arteries. IVA and METO similarly reduced (P < 0.05) 24-h HR by ≈15%, while PT had no impact. As expected, carotid artery stiffness increased (P < 0.05) in ATX mice compared with wild-type mice, while cerebral artery stiffness decreased (P < 0.05); this paradoxical increase in cerebrovascular compliance was associated with endothelial dysfunction and an augmented metalloproteinase-9 (MMP-9) activity (P < 0.05), without changing the lipid composition of the wall. Reducing HR (IVA and METO) limited carotid artery stiffening, but plaque progression was prevented by IVA only. In contrast, IVA maintained and PT improved cerebral endothelial nitric oxide synthase-dependent flow-mediated dilation and wall compliance, and both interventions reduced MMP-9 activity (P < 0.05); METO worsened endothelial dysfunction and compliance and did not reduce MMP-9 activity. In conclusion, HR-dependent mechanical stress contributes to carotid artery wall stiffening in severely dyslipidemic mice while cerebrovascular compliance is mostly regulated by the endothelium.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Virginie
authors.initials: V
authors.lastname: Bolduc
authors.forename: Annick
authors.initials: A
authors.lastname: Drouin
authors.forename: Marc-Antoine
authors.initials: MA
authors.lastname: Gillis
authors.forename: Natacha
authors.initials: N
authors.lastname: Duquette
authors.forename: Nathalie
authors.initials: N
authors.lastname: Thorin-Trescases
authors.forename: Isabelle
authors.initials: I
authors.lastname: Frayne-Robillard
authors.forename: Christine
authors.initials: C
authors.lastname: Des Rosiers
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.forename: Eric
authors.initials: E
authors.lastname: Thorin
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D001552:Benzazepines / Q000494:pharmacology; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D002340:Carotid Artery Diseases / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D002561:Cerebrovascular Disorders / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D003187:Compliance; D004195:Disease Models, Animal; D018450:Disease Progression; D050171:Dyslipidemias / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005081:Exercise Therapy; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D000077550:Ivabradine; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008790:Metoprolol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010641:Phenotype; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012720:Severity of Illness Index; D013314:Stress, Mechanical; D013997:Time Factors; D014664:Vasodilation
chemical_list: D000889:Anti-Arrhythmia Agents; D001055:Apolipoproteins B; D001552:Benzazepines; D011973:Receptors, LDL; D009569:Nitric Oxide; D000077550:Ivabradine; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D008790:Metoprolol