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Hypertension. 2001;37:604-608

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(Hypertension. 2001;37:604.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Expression of Cell Cycle Proteins in Blood Vessels of Angiotensin II–Infused Rats

Role of AT1 Receptors

Quy N. Diep; Mohammed El Mabrouk; Rhian M. Touyz; Ernesto L. Schiffrin

From the Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Quebec, Canada.

Correspondence to Ernesto L. Schiffrin, MD, Clinical Research Institute of Montreal, 110 Pine Ave W, Montreal, Quebec, Canada H2W 1R7. E-mail schiffe{at}IRCM.qc.ca


*    Abstract
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 *Abstract
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Angiotensin II is an important modulator of cell growth through AT1 receptors, as demonstrated both in vivo and in vitro. We investigated the role of proteins involved in the cell cycle, including cyclin D1, cyclin-dependent kinase 4 (cdk4), and cyclin-dependent kinase inhibitors p21 and p27 in blood vessels of angiotensin II–infused rats and the effect therein of the AT1-receptor antagonist losartan. Male Sprague-Dawley rats were infused for 7 days with angiotensin II (120 ng/kg per minute SC) and/or treated with losartan (10 mg/kg per day orally). DNA synthesis in mesenteric arteries was evaluated by radiolabeled 3H-thymidine incorporation. The expression of cyclin D1, cdk4, p21, and p27, which play critical roles during the G1-phase of the cell cycle process, was examined by Western blot analysis. Tail-cuff systolic blood pressure (mm Hg) was elevated (P<0.01, n=9) in angiotensin II–infused rats (161.3±8.2) versus control rats (110.1±5.3) and normalized by losartan (104.4±3.2). Radiolabeled 3H-thymidine incorporation (cpm/100 µg DNA) showed that angiotensin II infusion significantly increased DNA synthesis (152±5% versus 102±6% of control rats, P<0.05). Expression of cyclin D1 and cdk4 was significantly increased in the angiotensin II group to 213.7±8% and 263.6±37% of control animals, respectively, whereas expression of p21 and p27 was significantly decreased in the angiotensin II group to 23.2±10.4% and 10.3±5.3% of control animals, respectively. These effects induced by angiotensin II were normalized in the presence of losartan. Thus, when AT1 receptors are stimulated in vivo, DNA synthesis is enhanced in blood vessels by activation of cyclin D1 and cdk4. Reduction in cell cycle kinase inhibitors p21 and p27 may contribute to activation of growth induced by in vivo AT1 receptor stimulation.


Key Words: vasculature • muscle, smooth • hyperplasia • remodeling


*    Introduction
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During development of hypertension, resistance arteries undergo structural changes (remodeling) as an adaptation to increased wall stress.1 Vascular smooth muscle cell (VSMC) proliferation is one of the important processes for vascular remodeling.2 In blood vessels, angiotensin (Ang) II, the most important peptide mediating the effects of the renin-angiotensin system, contributes to development of structure remodeling through its growth factor properties on VSMCs.3 4 Ang II binds to its specific heterotrimeric G- protein–coupled receptors, AT1 receptors,5 6 and exerts its biological effects by modulating intracellular signaling pathways, including activation of phospholipase C, generation of inositol trisphosphate, diacylglycerol, Ca2+, protein kinase C, tyrosine kinases, Ras, Raf, and mitogen-activated protein kinases,7 8 9 10 11 12 13 which in turn increase various immediate-early genes, such as c-fos, c-jun, and c-myc14 15 16 and DNA synthesis.

Activation of VSMCs with Ang II has been shown to result in entry of cells into the cell cycle.17 A network of biochemical pathways that ensure that each cell cycle event occurs in proper sequence controls cell cycle progression.18 Progression through the G1 phase requires growth factor–induced signals and must converge, in late G1, on the cell cycle machinery to ensure the commitment of cells to enter the S phase. The G1 phase is regulated, at least in part, by the action of cyclin-dependent kinases (cdks) and their regulatory cyclin subunits.19 20 Cyclin C, cyclins D1, D2, and D3, and cyclin E play important roles in the G1 phase. Cyclin A is a key molecule in the S and G2/M phases; cyclin B is essential in the G2/M phase. A regulatory subunit of the G1 phase, cyclin D1, forms a complex with the catalytic partners cdk4 or cdk6 to form an active holoenzyme that phosphorylates pRB.21 22 23 Cyclin D1 is required for progression of the G1 phase and is therefore a critical target for proliferative signals in G1.21 22 Cyclin D1 expression is induced by several different growth factors including colony stimulating factor-1, epidermal growth factor, and Ang II.24 25 26 27 It has been shown in cultured cell lines that the cyclin D–cdk4/cdk6 complex regulates G1 progression, the cyclin E/cyclin A–cdk2 complex is essential for G1/S transition, and cyclin A/cyclin B–cdc2 (cdk1) promotes entry into mitosis. Activity of cdks is regulated not only by binding of cyclins but also by phosphorylation of threonine and tyrosine residues and by binding of cdk inhibitors, such as p21, p27, p57, and the INK4 family.28 29 30 Although the molecular mechanisms of cell cycle regulation have been extensively studied, it is not fully understood how Ang II starts the cell cycle regulatory machinery.

How Ang II induces cellular proliferation and DNA synthesis in VSMCs and a role for cyclin D1 and cdk4 in Ang II signaling in vivo, to our knowledge, has not been examined. We used Ang II–infused rats as a model to examine the effect of Ang II on proliferation of smooth muscle cells from small vessels in vivo and to investigate the role of cell cycle proteins in the Ang II–induced proliferative response. Blockade of AT1 receptors was used to determine the role of AT1 receptors in Ang–II induced proliferation.


*    Methods
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Animal Experiments
The study was approved by the Animal Care Committee of the Clinical Research Institute of Montreal and was performed according to the guidelines of the Canadian Council for Animal Care. As previously described,31 male Sprague-Dawley rats 7 weeks of age (weight, 200 g; n=9) were infused subcutaneously with Alzet osmotic minipumps (Alza Corp) with Ile5 –Ang II (Peninsula) at a dose of 120 ng/kg per minute. Losartan (AT1 receptor antagonist) was given in the drinking water at a dose of 10 mg/kg per day. After 7 days of treatment, systolic blood pressure (SBP) was measured by the tail-cuff method. Rats were killed by decapitation. The entire mesenteric bed was dissected, cleaned of fat and adventitia, and immediately frozen in dry ice and kept at -70°C until it was studied. The fraction of smooth muscle cells present in the samples exceeds 85%.

Evaluation of DNA Synthesis
DNA synthesis in mesenteric arteries was evaluated by radiolabeled 3H-thymidine incorporation. Rats were given an intraperitoneal injection of [methyl-3H]thymidine (0.5 mCi/kg, ICN Biomedicals Inc) 24 hours before being killed. DNA was extracted by phenol and chloroform as previously described.31 DNA concentration was determined by spectrophotometry. Equal amounts of DNA (100 µg) were counted by scintillation counter. DNA specific activity (cpm/100 µg DNA) reflects the incorporation of 3H-thymidine into smooth muscle DNA over the last 24 hours in vivo.

Western Blot Analysis of Cyclin D1, cdk4, p21, and p27
Protein was extracted from frozen tissue as previously described.31 Protein concentration was determined by the BioRad protein assay (Bio-Rad Laboratories Inc). Equal amounts of protein were separated by electrophoresis on a 15% polyacrylamide gel at 100 V for 1 hour and transferred onto a polyvinylidene difluoride membrane in a cooling system at 100 V for 1 hour. Membranes were incubated with specific antibody to cyclin D1, cdk4, p21, and p27 (Santa Cruz Biotechnology Inc) at a dilution 1:500, 1:1500, 1:500, and 1:1000, respectively, for 1 hour at room temperature. Signals were revealed with chemiluminescence and visualized by autoradiography.

Statistical Analysis
Results are presented as mean±SEM. Data were analyzed by 1-way ANOVA followed by a Newman-Keuls test. A value of P<0.05 was considered statistically significant.


*    Results
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Body Weight and SBP
Body weight was unchanged in Ang II–infused rats treated with or without losartan compared with normotensive rats (Table). The increase in SBP induced by Ang II infusion (P<0.01 versus control) was completely prevented by treatment with losartan (Table). Treatment of normotensive rats with losartan alone had no effect on SBP and body weight.


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  		Table 1. Body Weight and Blood Pressure of Rats Treated or Not Treated With Ang II With or Without Losartan

DNA Synthesis
Figure 1 shows a significant increase in DNA synthesis as demonstrated by increased 3H-thymidine incorporation in the Ang II–infused group (152.0±5.0%) in comparison to control rats (102±6%, P<0.05). In Ang–II infused rats that received losartan, DNA synthesis was similar to that of control rats (108.5±5.9%). Losartan alone decreased DNA synthesis slightly (to 80.7±3.3%).



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  		Figure 1. Bar graph shows 3H-thymidine incorporation into DNA from mesenteric arteries from each group expressed as percent of control (Ctrl). Los indicates losartan. Error bars indicate SEM (n=4). *P<0.05 vs control.

Expression of Cell Cycle Proteins
Expression of cyclin D1 and cdk4 was increased 2- to 3-fold in Ang II–infused rats compared with normotensive rats (Figures 2 and 3). Expression of cyclin D1 was similar to that of control rats in Ang–II infused rats treated with losartan (Figure 2). However, the expression of cdk4 was slightly reduced but not back to normal levels. Losartan on its own had no effect on expression of cyclin D1 or cdk4. As shown in Figures 4 and 5, expression of p21 and p27 was reduced to 23.2±10.4% and 10.3±5.3% of that in control rats. Losartan-treated Ang II–infused rats exhibited normal levels of p27 (78.3±15.6%). However, the expression of p21 in Ang II–infused rats treated with losartan did not return to normal. Losartan alone did not affect the expression of p21 but reduced the expression of p27.



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  		Figure 2. Top, Representative Western blot of cyclin D1. Ctrl indicates control; Los, losartan. Bottom, Bar graph shows mean±SEM of results from 3 rats. *P<0.05 vs control.



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  		Figure 3. Top, Representative Western blot of cdk4. Ctrl indicates control; Los, losartan. Bottom, Bar graph shows mean±SEM of results from 3 rats. *P<0.05 vs control.



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  		Figure 4. Top, Representative Western blot of p21. Ctrl indicates control; Los, losartan. Bottom, Bar graph shows mean±SEM of results from 3 rats. *P<0.05 vs control.



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  		Figure 5. Top, Representative Western blot of p27. Ctrl indicates control; Los, losartan. Bottom, Bar graph shows mean±SEM of results from 3 rats. *P<0.05 vs control.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
To evaluate the hypothesis that AT1-receptor–induced smooth muscle cell growth in vivo is associated with increased cell proliferation (DNA synthesis) and changes in cell cycle, particularly the G1 phase, we examined Ang II–infused rats treated without or with the AT1 receptor antagonist losartan. Our results show that AT1 stimulation is associated with enhanced proliferation of smooth muscle cells in resistance arteries of rats, as shown by increased DNA synthesis. Furthermore, we also show that AT1-receptor activation induces proliferation in blood vessels by stimulating cyclin D1 and cyclin-dependent kinases (cdk4) in G1 phase of cell cycle. These findings extend our understanding of the role of Ang II and its receptors, particularly AT1 receptors, as important contributors and regulators of cell growth contributing to vascular remodeling in hypertension.

Ang II–induced increase in 3H-thymidine uptake was completely inhibited by the AT1 receptor antagonist losartan, suggesting that Ang II–induced proliferation was mostly mediated by AT1 receptors. Our results also showed that the increase in cyclin D1 and cdk4 induced by Ang II was reversed to normal levels in the presence of losartan, which suggests that Ang II through AT1 receptors stimulates DNA synthesis by regulating cyclin D1 and cdk4. However, Ang II–induced downregulation of p21 was not inhibited by losartan. Thus, regulation of p21 may occur by other mechanisms, independent of AT1 receptors.

In addition to their contractile function, VSMCs can increase their mass through cellular proliferation, cellular hypertrophy, and production of extracellular matrix proteins. Changes in growth rates occur normally during development of the vascular system and after vascular injury but also under pathological conditions such as hypertension.32 In animal models of hypertension, the increase in vascular mass has been reported to be associated primarily with SMC hypertrophy in large arteries and with hyperplasia or proliferation in small resistance vessels. The growth response of VSMCs is clearly dependent on the nature of the growth stimulus. There is evidence that Ang II induces both cellular hypertrophy and cellular hyperplasia as a result of increased protein and DNA synthesis, respectively. Still, much remains to be learned about the molecular determinants of vascular SMC hypertrophic versus hyperplastic growth responses, particularly in vivo. In cell culture, previous studies have shown that Ang II induced cell growth by stimulation of cyclin D1.17 27 However, it has also been shown that Ang II induces cell cycle entry but fails to downregulate the level of p27 protein,17 33 resulting in blocking of the progression through the cell cycle toward DNA synthesis and mitosis. It has been speculated that not only may commitment to hyperplasia versus hypertrophy be made during the G1 phase, but the response to stimuli of cellular activation and programmed cell death may also be affected by early cell-cycle entry. Our present study shows that Ang II increases DNA synthesis by decreasing expression of p21 and p27. In the presence of losartan, the change in DNA synthesis, cyclin D1, cdk4, and p27 was completely or partly reversed. However, the expression of p21 remains the same in the Ang II group with or without losartan, suggesting that p21 may play a role not only in DNA synthesis but also protein synthesis. A previous study has also shown that Ang II, through AT1 receptors, may simultaneously induce cell growth and apoptosis, although the latter may be a reactive response to cell growth independent of direct effects of AT1 receptors and involving different molecular mechanisms.31 We have also shown that Ang II stimulated DNA synthesis by increasing expression of cyclin D1 and cdk4. Cyclin D1–cdk4 complexes promote G1 phase progression through phosphorylation and inactivation of the retinoblastoma (Rb) gene product.30 34 However, the role of Rb in Ang II–stimulated DNA synthesis in vivo remains to be clarified. The extent to which normalization of cell-cycle protein expression by AT1 antagonism with losartan results from blood pressure reduction or blockade of Ang II effects is unclear. Answering this question will require comparison with results of blood pressure reduction with agents that do not block Ang II action.

Conclusions
We have investigated molecular steps involved in the cell cycle induced by Ang II in resistance arteries. Cell growth in blood vessels, which may play an important role in vascular remodeling in hypertension, may be regulated in vivo by Ang receptors, specifically by AT1 receptors, starting cell cycle progression. Activation of AT1 receptors in vivo in rats results in SBP increase and blood vessel growth as well by stimulation of cyclin D1 and cdk4 in the cell cycle. Thus, the present results extend our knowledge on the essential role of AT1 receptors in blood pressure control and VSMC growth, as shown by increases in blood pressure, cell proliferation, and expression of cyclin D1 and cdk4.


*    Acknowledgments
 
This work was supported by a Group Grant from the Medical Research Council of Canada (now the Canadian Institutes of Health Research) to the Multidisciplinary Research Group on Hypertension. Dr Q.N. Diep holds a postdoctoral fellowship from the Canadian Institutes of Health Research. The authors are grateful to Suzanne Diebold for excellent technical assistance.

Received October 24, 2000; first decision November 20, 2000; accepted December 8, 2000.


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