title: Aortic and carotid arterial stiffness and epigenetic regulator gene expression changes precede blood pressure rise in stroke-prone Dahl salt-sensitive hypertensive rats.
abstract: Multiple clinical studies show that arterial stiffness, measured as pulse wave velocity (PWV), precedes hypertension and is an independent predictor of hypertension end organ diseases including stroke, cardiovascular disease and chronic kidney disease. Risk factor studies for arterial stiffness implicate age, hypertension and sodium. However, causal mechanisms linking risk factor to arterial stiffness remain to be elucidated. Here, we studied the causal relationship of arterial stiffness and hypertension in the Na-induced, stroke-prone Dahl salt-sensitive (S) hypertensive rat model, and analyzed putative molecular mechanisms. Stroke-prone and non-stroke-prone male and female rats were studied at 3- and 6-weeks of age for arterial stiffness (PWV, strain), blood pressure, vessel wall histology, and gene expression changes. Studies showed that increased left carotid and aortic arterial stiffness preceded hypertension, pulse pressure widening, and structural wall changes at the 6-week time-point. Instead, differential gene induction was detected implicating molecular-functional changes in extracellular matrix (ECM) structural constituents, modifiers, cell adhesion, and matricellular proteins, as well as in endothelial function, apoptosis balance, and epigenetic regulators. Immunostaining testing histone modifiers Ep300, HDAC3, and PRMT5 levels confirmed carotid artery-upregulation in all three layers: endothelial, smooth muscle and adventitial cells. Our study recapitulates observations in humans that given salt-sensitivity, increased Na-intake induced arterial stiffness before hypertension, increased pulse pressure, and structural vessel wall changes. Differential gene expression changes associated with arterial stiffness suggest a molecular mechanism linking sodium to full-vessel wall response affecting gene-networks involved in vascular ECM structure-function, apoptosis balance, and epigenetic regulation.
authors.affiliation: Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Herrera
authors.affiliation: Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Julius L
authors.initials: JL
authors.lastname: Decano
authors.affiliation: Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Giordano
authors.affiliation: Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Moran
authors.affiliation: Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Nelson
authors.initials: N
authors.lastname: Ruiz-Opazo
mesh_terms: D063194:Adventitia / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology*; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D020022:Genetic Predisposition to Disease; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology; D008297:Male; D010641:Phenotype; D063177:Pulse Wave Analysis; D051381:Rats; D020303:Rats, Inbred Dahl; D012982:Sodium, Dietary / Q000009:adverse effects; D020521:Stroke / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology*; D017540:Tunica Media / Q000187:drug effects / Q000378:metabolism; D014463:Ultrasonography; D059289:Vascular Stiffness / Q000187:drug effects
chemical_list: D012982:Sodium, Dietary