title: Cks1 mediates vascular smooth muscle cell polyploidization.
abstract: Vascular smooth muscle cells (VSMC) at capacitance arteries of hypertensive individuals and animals undergo dramatic polyploidization that contributes toward their hypertrophic phenotype. We report here the identification of a defective mitotic spindle cell cycle checkpoint in VSMC isolated from capacitance arteries of pre-hypertensive rats. These cells demonstrated a high predisposition to polyploidization in culture and failed to maintain cyclin B protein levels in response to colcemid, a mitotic inhibitor. Furthermore, this altered mitotic spindle checkpoint status was associated with the overexpression of Cks1, a Cdc2 adapter protein that promotes cyclin B degradation. Cks1 up-regulation, cyclin B down-regulation, and VSMC polyploidization were evidenced at the smooth muscle of capacitance arteries of genetically hypertensive and Goldblatt-operated rats. In addition, angiotensin II infusion dramatically increased Cks1 protein levels at capacitance arteries of normotensive rats, and angiotensin II treatment of isolated VSMC abrogated their ability to down-regulate Cks1 and maintain cyclin B protein expression in response to colcemid. Finally, transduction of VSMC from normotensive animals with a retrovirus that drives the expression of Cks1 was sufficient to alter their mitotic spindle cell cycle checkpoint status and promote unscheduled cyclin B metabolism, cell cycle re-entry, and polyploidization. These data demonstrate that Cks1 regulates cyclin B metabolism and ploidy in VSMC and may contribute to the understanding of the phenomena of VSMC polyploidization during hypertension.
authors.affiliation: Departments of Genetics and Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Hixon
authors.forename: C
authors.initials: C
authors.lastname: Obejero-Paz
authors.forename: C
authors.initials: C
authors.lastname: Muro-Cacho
authors.forename: M W
authors.initials: MW
authors.lastname: Wagner
authors.forename: E
authors.initials: E
authors.lastname: Millie
authors.forename: J
authors.initials: J
authors.lastname: Nagy
authors.forename: T J
authors.initials: TJ
authors.lastname: Hassold
authors.forename: A
authors.initials: A
authors.lastname: Gualberto
mesh_terms: D000818:Animals; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D010641:Phenotype; D011123:Polyploidy; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
chemical_list: D018844:Cyclin-Dependent Kinases