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• W2000619540 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. 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. vascular smooth muscle cells spontaneously hypertensive rats Wistar Kyoto cyclin kinase subunit 1 population doubling analysis of variance fetal bovine serum proliferating cell nuclear antigen bromodeoxyuridine Hypertension is accompanied by changes in vascular smooth muscle cell (VSMC)1 growth that are specific for different vascular territories. Vascular smooth muscle hypertrophy predominates at capacitance arteries, those of high compliance, and is associated to VSMC polyploidization in hypertensive individuals (1Printseva O.Y. Tjurmin A.V. Am. J. Hypertens. 1992; 5: 118S-123SCrossref PubMed Scopus (12) Google Scholar) and animals (2Conyers R.B. Kwan C.Y. Lee R.M. J. Hypertens. 1995; 13: 507-515Crossref PubMed Scopus (12) Google Scholar, 3Devlin A.M. Davidson A.O. Gordon J.F. Campbell A.M. Morton J.J. Reid J.L. Dominiczak A.F. J. Hum. Hypertens. 1995; 9: 497-500PubMed Google Scholar, 4Owens G.K. Schwartz S.M. Circ. Res. 1982; 51: 280-289Crossref PubMed Scopus (277) Google Scholar, 5Owens G.K. Schwartz S.M. McCanna M. Hypertension. 1988; 11: 198-207Crossref PubMed Scopus (89) Google Scholar, 6Lee R.M. Conyers R.B. Kwan C.Y. Can. J. Physiol. Pharmacol. 1992; 70: 1496-1501Crossref PubMed Scopus (12) Google Scholar, 7Dominiczak A.F. Devlin A.M. Lee W.K. Anderson N.H. Bohr D.F. Reid J.L. Hypertension. 1996; 27: 752-759Crossref PubMed Google Scholar, 8Conyers R.B. Werstiuk E.S. Lee R.M. Can. J. Physiol. Pharmacol. 1997; 75: 375-382Crossref PubMed Scopus (3) Google Scholar). Tetraploid and octaploid VSMC of hypertensive rats have 2.4- and 4.8-fold, respectively, the protein content of diploid VSMC of normotensive rats (4Owens G.K. Schwartz S.M. Circ. Res. 1982; 51: 280-289Crossref PubMed Scopus (277) Google Scholar). Additionally, on a per cell basis, polyploid VSMC express higher levels of platelet-derived growth factor A, fibronectin, and collagen than their diploid counterparts (9van Neck J.W. van Berkel P.H. Telleman P. Steijns L.S. Onnekink C. Bloemers H.P. FEBS Lett. 1992; 297: 189-195Crossref PubMed Scopus (5) Google Scholar). Importantly, the hypertrophy of vascular smooth muscle at capacitance arteries causes arterial stiffness and promotes left ventricular overload and altered coronary blood perfusion (10Gatzka C.D. Cameron J.D. Kingwell B.A. Dart A.M. Hypertension. 1998; 32: 575-578Crossref PubMed Scopus (146) Google Scholar).Several stimuli, including catecholamines (11Leitschuh M. Chobanian A.V. Hypertension. 1987; 9: III106-III109Crossref PubMed Google Scholar, 12Yamori Y. Mano M. Nara Y. Horie R. Circulation. 1987; 75: I92-I95PubMed Google Scholar, 13Printseva O. Tjurmin A.V. Rudchenko S.A. Repin V.S. Exp. Cell Res. 1989; 184: 342-350Crossref PubMed Scopus (9) Google Scholar), angiotensin II (3Devlin A.M. Davidson A.O. Gordon J.F. Campbell A.M. Morton J.J. Reid J.L. Dominiczak A.F. J. Hum. Hypertens. 1995; 9: 497-500PubMed Google Scholar, 7Dominiczak A.F. Devlin A.M. Lee W.K. Anderson N.H. Bohr D.F. Reid J.L. Hypertension. 1996; 27: 752-759Crossref PubMed Google Scholar, 14Black M.J. Bertram J.F. Campbell J.H. Campbell G.R. J. Hypertens. 1995; 13: 683-692Crossref PubMed Scopus (35) Google Scholar), deoxycorticosterone/salt (11Leitschuh M. Chobanian A.V. Hypertension. 1987; 9: III106-III109Crossref PubMed Google Scholar, 15Lichtenstein A.H. Brecher P. Chobanian A.V. Hypertension. 1986; 8: II50-II54Crossref PubMed Google Scholar, 16Chobanian A.V. Lichtenstein A.H. Schwartz J.H. Hanspal J. Brecher P. Circulation. 1987; 75: I102-I106PubMed Google Scholar), and nitric-oxide synthase blockade (3Devlin A.M. Davidson A.O. Gordon J.F. Campbell A.M. Morton J.J. Reid J.L. Dominiczak A.F. J. Hum. Hypertens. 1995; 9: 497-500PubMed Google Scholar, 7Dominiczak A.F. Devlin A.M. Lee W.K. Anderson N.H. Bohr D.F. Reid J.L. Hypertension. 1996; 27: 752-759Crossref PubMed Google Scholar) are known to induce VSMC polyploidization. The effects of angiotensin II on VSMC ploidy have been extensively characterized. Infusion of angiotensin II in rats promotes VSMC polyploidization at large arteries (14Black M.J. Bertram J.F. Campbell J.H. Campbell G.R. J. Hypertens. 1995; 13: 683-692Crossref PubMed Scopus (35) Google Scholar). Additionally, activation of the renin-angiotensin system by occlusion of a renal artery, or Goldblatt's operation, increases aortic VSMC ploidy in these animals (17Owens G.K. Schwartz S.M. Circ. Res. 1983; 53: 491-501Crossref PubMed Scopus (130) Google Scholar). Moreover, treatment of spontaneously hypertensive rats (SHR) and its derivative strain stroke-prone SHR with angiotensin converting enzyme inhibitors or angiotensin II AT1 receptor blockers inhibits VSMC polyploidization (4Owens G.K. Schwartz S.M. Circ. Res. 1982; 51: 280-289Crossref PubMed Scopus (277) Google Scholar, 18Rosen E.M. Goldberg I.D. Shapiro H.M. Levenson S.E. Halpin P.A. J. Hypertens. Suppl. 1986; 4: S109-S111Crossref PubMed Scopus (41) Google Scholar, 19Black M.J. Campbell J.H. Campbell G.R. Blood Vessels. 1988; 25: 89-100PubMed Google Scholar). However, despite extensive investigation, the molecular mechanism(s) underlying VSMC polyploidization has eluded characterization.Mammalian cells are protected from cell cycle re-entry at mitosis by the activity of the mitotic spindle cell cycle checkpoint (20Cahill D.P. Lengauer C., Yu, J. Riggins G.J. Willson J.K. Markowitz S.D. Kinzler K.W. Vogelstein B. Nature. 1998; 392: 300-303Crossref PubMed Scopus (1303) Google Scholar, 21Cross S.M. Sanchez C.A. Morgan C.A. Schimke M.K. Ramel S. Idzerda R.L. Raskind W.H. Reid B.J. Science. 1995; 267: 1353-1356Crossref PubMed Scopus (675) Google Scholar, 22Gualberto A. Aldape K. Kozakiewicz K. Tlsty T.D. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5166-5171Crossref PubMed Scopus (204) Google Scholar). This pathway delays the exit from mitosis if the chromosomal segregation cannot be properly completed by preventing the inactivation of the M-phase promoting complex (Cdc2, cyclin B, and associated proteins) (23Murray A.W. Curr. Opin. Genet. Dev. 1995; 5: 5-11Crossref PubMed Scopus (138) Google Scholar, 24Rudner A.D. Murray A.W. Curr. Opin. Cell Biol. 1996; 8: 773-780Crossref PubMed Scopus (317) Google Scholar, 25Elledge S.J. Science. 1996; 274: 1664-1672Crossref PubMed Scopus (1756) Google Scholar). Recent data indicate that, in mammalian cells, M-phase growth arrest is accomplished in part by down-regulation of Cks1 (26Hixon M.L. Flores A.I. Wagner M.W. Gualberto A. Mol. Cell. Biol. 1998; 18: 6224-6237Crossref PubMed Scopus (15) Google Scholar), a Cdc2 adapter protein that promotes cyclin B metabolism (27Basi G. Draetta G. Mol. Cell. Biol. 1995; 15: 2028-2036Crossref PubMed Scopus (41) Google Scholar, 28Moreno S. Hayles J. Nurse P. Cell. 1989; 58: 361-372Abstract Full Text PDF PubMed Scopus (400) Google Scholar, 29Patra D. Dunphy W.G. Genes Dev. 1996; 10: 1503-1515Crossref PubMed Scopus (79) Google Scholar). Cells in which the mitotic checkpoint fails to down-regulate Cks1 expression cannot maintain cyclin B protein expression and M-phase growth arrest, and are predisposed to undergo cell cycle re-entry and polyploidization (26Hixon M.L. Flores A.I. Wagner M.W. Gualberto A. Mol. Cell. Biol. 1998; 18: 6224-6237Crossref PubMed Scopus (15) Google Scholar).The incidence of polyploidy in vascular smooth muscle of hypertensive individuals prompted us to investigate the activity of the mitotic spindle cell cycle checkpoint in VSMC. The status of this pathway was studied in cultures of VSMC isolated from multiple vascular beds of normal and hypertensive rats. We provide functional and biochemical evidence of a specific mitotic spindle cell cycle checkpoint defect in cultures of VSMC isolated from capacitance arteries of SHR. These cells express high levels of Cks1 protein and fail to down-regulate Cks1 in response to mitotic inhibitors. VSMC isolated from resistance arteries of SHR had low Cks1 expression and normal mitotic checkpoint status. Treatment of SHR with the angiotensin converting enzyme inhibitor captopril reduced Cks1 and ploidy levels in aortic smooth muscle. Furthermore, activation of the renin-angiotensin system in the normotensive rat strain WKY by renal artery clipping, or angiotensin II infusion, induced Cks1 protein levels and VSMC polyploidization at aortic smooth muscle. In addition, treatment of primary cultures of WKY VSMC with angiotensin II induced Cks1 up-regulation and failure to control cyclin B expression in response to a mitotic spindle inhibitor. Finally, ectopic expression of Cks1 in VSMC isolated from normotensive rats reproduced the altered mitotic spindle cell cycle checkpoint phenotype observed in VSMC of hypertensive rats. In summary, these data demonstrate that Cks1 regulates VSMC ploidy and suggest that Cks1 up-regulation may contribute to the phenomena of VSMC polyploidization during hypertension. Hypertension is accompanied by changes in vascular smooth muscle cell (VSMC)1 growth that are specific for different vascular territories. Vascular smooth muscle hypertrophy predominates at capacitance arteries, those of high compliance, and is associated to VSMC polyploidization in hypertensive individuals (1Printseva O.Y. Tjurmin A.V. Am. J. Hypertens. 1992; 5: 118S-123SCrossref PubMed Scopus (12) Google Scholar) and animals (2Conyers R.B. Kwan C.Y. Lee R.M. J. Hypertens. 1995; 13: 507-515Crossref PubMed Scopus (12) Google Scholar, 3Devlin A.M. Davidson A.O. Gordon J.F. Campbell A.M. Morton J.J. Reid J.L. Dominiczak A.F. J. Hum. Hypertens. 1995; 9: 497-500PubMed Google Scholar, 4Owens G.K. Schwartz S.M. Circ. Res. 1982; 51: 280-289Crossref PubMed Scopus (277) Google Scholar, 5Owens G.K. Schwartz S.M. McCanna M. Hypertension. 1988; 11: 198-207Crossref PubMed Scopus (89) Google Scholar, 6Lee R.M. Conyers R.B. Kwan C.Y. Can. J. Physiol. Pharmacol. 1992; 70: 1496-1501Crossref PubMed Scopus (12) Google Scholar, 7Dominiczak A.F. Devlin A.M. Lee W.K. Anderson N.H. Bohr D.F. Reid J.L. Hypertension. 1996; 27: 752-759Crossref PubMed Google Scholar, 8Conyers R.B. Werstiuk E.S. Lee R.M. Can. J. Physiol. Pharmacol. 1997; 75: 375-382Crossref PubMed Scopus (3) Google Scholar). Tetraploid and octaploid VSMC of hypertensive rats have 2.4- and 4.8-fold, respectively, the protein content of diploid VSMC of normotensive rats (4Owens G.K. Schwartz S.M. Circ. Res. 1982; 51: 280-289Crossref PubMed Scopus (277) Google Scholar). Additionally, on a per cell basis, polyploid VSMC express higher levels of platelet-derived growth factor A, fibronectin, and collagen than their diploid counterparts (9van Neck J.W. van Berkel P.H. Telleman P. Steijns L.S. Onnekink C. Bloemers H.P. FEBS Lett. 1992; 297: 189-195Crossref PubMed Scopus (5) Google Scholar). Importantly, the hypertrophy of vascular smooth muscle at capacitance arteries causes arterial stiffness and promotes left ventricular overload and altered coronary blood perfusion (10Gatzka C.D. Cameron J.D. Kingwell B.A. Dart A.M. Hypertension. 1998; 32: 575-578Crossref PubMed Scopus (146) Google Scholar). Several stimuli, including catecholamines (11Leitschuh M. Chobanian A.V. Hypertension. 1987; 9: III106-III109Crossref PubMed Google Scholar, 12Yamori Y. Mano M. Nara Y. Horie R. Circulation. 1987; 75: I92-I95PubMed Google Scholar, 13Printseva O. Tjurmin A.V. Rudchenko S.A. Repin V.S. Exp. Cell Res. 1989; 184: 342-350Crossref PubMed Scopus (9) Google Scholar), angiotensin II (3Devlin A.M. Davidson A.O. Gordon J.F. Campbell A.M. Morton J.J. Reid J.L. Dominiczak A.F. J. Hum. Hypertens. 1995; 9: 497-500PubMed Google Scholar, 7Dominiczak A.F. Devlin A.M. Lee W.K. Anderson N.H. Bohr D.F. Reid J.L. Hypertension. 1996; 27: 752-759Crossref PubMed Google Scholar, 14Black M.J. Bertram J.F. Campbell J.H. Campbell G.R. J. Hypertens. 1995; 13: 683-692Crossref PubMed Scopus (35) Google Scholar), deoxycorticosterone/salt (11Leitschuh M. Chobanian A.V. Hypertension. 1987; 9: III106-III109Crossref PubMed Google Scholar, 15Lichtenstein A.H. Brecher P. Chobanian A.V. Hypertension. 1986; 8: II50-II54Crossref PubMed Google Scholar, 16Chobanian A.V. Lichtenstein A.H. Schwartz J.H. Hanspal J. Brecher P. Circulation. 1987; 75: I102-I106PubMed Google Scholar), and nitric-oxide synthase blockade (3Devlin A.M. Davidson A.O. Gordon J.F. Campbell A.M. Morton J.J. Reid J.L. Dominiczak A.F. J. Hum. Hypertens. 1995; 9: 497-500PubMed Google Scholar, 7Dominiczak A.F. Devlin A.M. Lee W.K. Anderson N.H. Bohr D.F. Reid J.L. Hypertension. 1996; 27: 752-759Crossref PubMed Google Scholar) are known to induce VSMC polyploidization. The effects of angiotensin II on VSMC ploidy have been extensively characterized. Infusion of angiotensin II in rats promotes VSMC polyploidization at large arteries (14Black M.J. Bertram J.F. Campbell J.H. Campbell G.R. J. Hypertens. 1995; 13: 683-692Crossref PubMed Scopus (35) Google Scholar). Additionally, activation of the renin-angiotensin system by occlusion of a renal artery, or Goldblatt's operation, increases aortic VSMC ploidy in these animals (17Owens G.K. Schwartz S.M. Circ. Res. 1983; 53: 491-501Crossref PubMed Scopus (130) Google Scholar). Moreover, treatment of spontaneously hypertensive rats (SHR) and its derivative strain stroke-prone SHR with angiotensin converting enzyme inhibitors or angiotensin II AT1 receptor blockers inhibits VSMC polyploidization (4Owens G.K. Schwartz S.M. Circ. Res. 1982; 51: 280-289Crossref PubMed Scopus (277) Google Scholar, 18Rosen E.M. Goldberg I.D. Shapiro H.M. Levenson S.E. Halpin P.A. J. Hypertens. Suppl. 1986; 4: S109-S111Crossref PubMed Scopus (41) Google Scholar, 19Black M.J. Campbell J.H. Campbell G.R. Blood Vessels. 1988; 25: 89-100PubMed Google Scholar). However, despite extensive investigation, the molecular mechanism(s) underlying VSMC polyploidization has eluded characterization. Mammalian cells are protected from cell cycle re-entry at mitosis by the activity of the mitotic spindle cell cycle checkpoint (20Cahill D.P. Lengauer C., Yu, J. Riggins G.J. Willson J.K. Markowitz S.D. Kinzler K.W. Vogelstein B. Nature. 1998; 392: 300-303Crossref PubMed Scopus (1303) Google Scholar, 21Cross S.M. Sanchez C.A. Morgan C.A. Schimke M.K. Ramel S. Idzerda R.L. Raskind W.H. Reid B.J. Science. 1995; 267: 1353-1356Crossref PubMed Scopus (675) Google Scholar, 22Gualberto A. Aldape K. Kozakiewicz K. Tlsty T.D. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5166-5171Crossref PubMed Scopus (204) Google Scholar). This pathway delays the exit from mitosis if the chromosomal segregation cannot be properly completed by preventing the inactivation of the M-phase promoting complex (Cdc2, cyclin B, and associated proteins) (23Murray A.W. Curr. Opin. Genet. Dev. 1995; 5: 5-11Crossref PubMed Scopus (138) Google Scholar, 24Rudner A.D. Murray A.W. Curr. Opin. Cell Biol. 1996; 8: 773-780Crossref PubMed Scopus (317) Google Scholar, 25Elledge S.J. Science. 1996; 274: 1664-1672Crossref PubMed Scopus (1756) Google Scholar). Recent data indicate that, in mammalian cells, M-phase growth arrest is accomplished in part by down-regulation of Cks1 (26Hixon M.L. Flores A.I. Wagner M.W. Gualberto A. Mol. Cell. Biol. 1998; 18: 6224-6237Crossref PubMed Scopus (15) Google Scholar), a Cdc2 adapter protein that promotes cyclin B metabolism (27Basi G. Draetta G. Mol. Cell. Biol. 1995; 15: 2028-2036Crossref PubMed Scopus (41) Google Scholar, 28Moreno S. Hayles J. Nurse P. Cell. 1989; 58: 361-372Abstract Full Text PDF PubMed Scopus (400) Google Scholar, 29Patra D. Dunphy W.G. Genes Dev. 1996; 10: 1503-1515Crossref PubMed Scopus (79) Google Scholar). Cells in which the mitotic checkpoint fails to down-regulate Cks1 expression cannot maintain cyclin B protein expression and M-phase growth arrest, and are predisposed to undergo cell cycle re-entry and polyploidization (26Hixon M.L. Flores A.I. Wagner M.W. Gualberto A. Mol. Cell. Biol. 1998; 18: 6224-6237Crossref PubMed Scopus (15) Google Scholar). The incidence of polyploidy in vascular smooth muscle of hypertensive individuals prompted us to investigate the activity of the mitotic spindle cell cycle checkpoint in VSMC. The status of this pathway was studied in cultures of VSMC isolated from multiple vascular beds of normal and hypertensive rats. We provide functional and biochemical evidence of a specific mitotic spindle cell cycle checkpoint defect in cultures of VSMC isolated from capacitance arteries of SHR. These cells express high levels of Cks1 protein and fail to down-regulate Cks1 in response to mitotic inhibitors. VSMC isolated from resistance arteries of SHR had low Cks1 expression and normal mitotic checkpoint status. Treatment of SHR with the angiotensin converting enzyme inhibitor captopril reduced Cks1 and ploidy levels in aortic smooth muscle. Furthermore, activation of the renin-angiotensin system in the normotensive rat strain WKY by renal artery clipping, or angiotensin II infusion, induced Cks1 protein levels and VSMC polyploidization at aortic smooth muscle. In addition, treatment of primary cultures of WKY VSMC with angiotensin II induced Cks1 up-regulation and failure to control cyclin B expression in response to a mitotic spindle inhibitor. Finally, ectopic expression of Cks1 in VSMC isolated from normotensive rats reproduced the altered mitotic spindle cell cycle checkpoint phenotype observed in VSMC of hypertensive rats. In summary, these data demonstrate that Cks1 regulates VSMC ploidy and suggest that Cks1 up-regulation may contribute to the phenomena of VSMC polyploidization during hypertension. We thank Paul E. DiCorleto, Janice F. Douglas, Antonio Scarpa, and Kenneth Walsh for reagents and suggestions." @default.
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• W2000619540 title "Cks1 Mediates Vascular Smooth Muscle Cell Polyploidization" @default.
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