title: Chronic antihypertensive treatment improves pulse pressure but not large artery mechanics in a mouse model of congenital vascular stiffness.
abstract: Increased arterial stiffness is a common characteristic of humans with Williams-Beuren syndrome and mouse models of elastin insufficiency. Arterial stiffness is associated with multiple negative cardiovascular outcomes, including myocardial infarction, stroke, and sudden death. Therefore, identifying therapeutic interventions that improve arterial stiffness in response to changes in elastin levels is of vital importance. The goal of this study was to determine the effect of chronic pharmacologic therapy with different classes of antihypertensive medications on arterial stiffness in elastin insufficiency. Elastin-insufficient mice 4-6 wk of age and wild-type littermates were subcutaneously implanted with osmotic micropumps delivering a continuous dose of one of the following: vehicle, losartan, nicardipine, or propranolol for 8 wk. At the end of treatment period, arterial blood pressure and large artery compliance and remodeling were assessed. Our results show that losartan and nicardipine treatment lowered blood pressure and pulse pressure in elastin-insufficient mice. Elastin and collagen content of abdominal aortas as well as ascending aorta and carotid artery biomechanics were not affected by any of the drug treatments in either genotype. By reducing pulse pressure and shifting the working pressure range of an artery to a more compliant region of the pressure-diameter curve, antihypertensive medications may mitigate the consequences of arterial stiffness, an effect that is drug class independent. These data emphasize the importance of early recognition and long-term management of hypertension in Williams-Beuren syndrome and elastin insufficiency.
authors.affiliation: Departments of Pediatrics Washington University School of Medicine, St. Louis, Missouri; and.
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Halabi
authors.affiliation: Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Broekelmann
authors.affiliation: Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Russell H
authors.initials: RH
authors.lastname: Knutsen
authors.affiliation: Departments of Pediatrics Washington University School of Medicine, St. Louis, Missouri; and.
authors.forename: Li
authors.initials: L
authors.lastname: Ye
authors.affiliation: Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mecham
authors.affiliation: Departments of Pediatrics Washington University School of Medicine, St. Louis, Missouri; and kozel_b@kids.wustl.edu.
authors.forename: Beth A
authors.identifier: http://orcid.org/0000-0002-9757-7118
authors.initials: BA
authors.lastname: Kozel
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001158:Arteries / Q000187:drug effects* / Q000503:physiopathology; D001794:Blood Pressure; D004549:Elastin / Q000172:deficiency / Q000235:genetics; D019808:Losartan / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D009529:Nicardipine / Q000627:therapeutic use; D011433:Propranolol / Q000627:therapeutic use; D059289:Vascular Stiffness / Q000187:drug effects* / Q000235:genetics; D018980:Williams Syndrome / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D000959:Antihypertensive Agents; D004549:Elastin; D011433:Propranolol; D009529:Nicardipine; D019808:Losartan
keywords: Williams-Beuren syndrome; arterial stiffness; elastin; hypertension; pulse pressure