Cks1 mediates vascular smooth muscle cell polyploidization.
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.
Hixon
M L
ML
Departments of Genetics and Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
Obejero-Paz
C
C
Muro-Cacho
C
C
Wagner
M W
MW
Millie
E
E
Nagy
J
J
Hassold
T J
TJ
Gualberto
A
A
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
D018844:Cyclin-Dependent Kinases