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(Hypertension. 2000;35:1069.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Proapoptotic and Growth-Inhibitory Role of Angiotensin II Type 2 Receptor in Vascular Smooth Muscle Cells of Spontaneously Hypertensive Rats In Vivo

Bun-Seng Tea; Shant Der Sarkissian; Rhian M. Touyz; Pavel Hamet; Denis deBlois

From the Centre de Recherche, Centre Hospitaliér de l’Université de Montréal (CHUM) (B.-S. T., S.D.S., P.H., D.D.), Montreal, Quebec, Canada, and The Clinical Research Institute of Montreal (R.M.T.).

Correspondence to Denis deBlois, Centre de Recherche, CHUM–Hôtel-Dieu, 3840 St Urbain St, Room 7-132B, Montreal, Quebec H2W 1T8, Canada. E-mail debloisd{at}pharmco.umontreal.ca

Abstract—Angiotensin type 2 (AT₂) receptors for angiotensin II suppress cell growth and induce apoptosis in vitro, but their role is poorly defined in vivo. We reported that transient induction of smooth muscle cell (SMC) apoptosis precedes DNA synthesis inhibition and aortic hypertrophy regression in spontaneously hypertensive rats treated with the AT₁ antagonist losartan or the converting-enzyme inhibitor enalapril. Although both drugs are equipotent in reducing SMC number, apoptosis occurs significantly earlier with losartan than enalapril. To examine the role of AT₂ receptors in this model, spontaneously hypertensive rats were given valsartan, an AT₁ antagonist, or enalapril, in combination or not with the AT₂ antagonist PD123319 for 1 or 2 weeks. Control rats received vehicle. Systolic blood pressure was reduced similarly by valsartan and enalapril but it was not significantly affected by PD123319. Angiotensin II plasma levels were increased (6-fold) with valsartan and reduced (80%) with enalapril but unaffected by PD123319. Valsartan significantly increased internucleosomal DNA fragmentation indicative of apoptosis at 1 week only (2.7-fold) and significantly reduced aortic mass (18%), SMC number (33%), and DNA synthesis (24%, measured by ³H-thymidine incorporation) at 2 weeks. These valsartan-induced changes were prevented by PD123319. In contrast, enalapril-induced DNA fragmentation (2-fold increase at 2 weeks) was not affected by PD123319. PD123319 given alone did not affect growth or apoptosis. AT₁ and AT₂ receptor mRNAs were detected in the aorta by reverse transcription–polymerase chain reaction. Together, these results provide the first evidence that AT₂ receptors mediate vascular mass regression by stimulating SMC apoptosis in vivo, an effect seen during AT₁ receptor blockade but not during converting-enzyme inhibition.

Key Words: angiotensin II • muscle, smooth, vascular • losartan • enalapril

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