Proapoptotic and growth-inhibitory role of angiotensin II type 2 receptor in vascular smooth muscle cells of spontaneously hypertensive rats in vivo

Angiotensin type 2 (AT(2)) receptors for angiotensin II suppress cell growt h 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 spon taneously hypertensive rats treated with the AT(1) antagonist losartan or t he converting-enzyme inhibitor enalapril. Although both drugs are equipoten t in reducing SMC number, apoptosis occurs significantly earlier with losar tan than enalapril, To examine the role of AT(2) receptors in this model, s pontaneously hypertensive rats were given valsartan, an AT(1) antagonist, o r enalapril, in combination or not with the AT(2) antagonist PD123319 for 1 or 2 weeks. Control rats received vehicle. Systolic blood pressure was red uced similarly by valsartan and enalapril but it was not significantly affe cted by PD123319. Angiotensin II plasma levels were increased (6-fold) with valsartan and reduced (80%) with enalapril but unaffected by PD123319. Val sartan significantly increased internucleosomal DNA fragmentation indicativ e of apoptosis at 1 week only (2.7-fold) and significantly reduced aortic m ass (18%), SMC number (33%), and DNA synthesis (24%, measured by H-3-thymid ine incorporation) at 2 weeks. These valsartan-induced changes were prevent ed by PD123319. In contrast, enalapril-induced DNA fragmentation (2-fold in crease at 2 weeks) was not affected by PD123319. PD123319 given alone did n ot affect growth or apoptosis, AT(1) and AT(2) receptor mRNAs were detected in the aorta by reverse transcription-polymerase chain reaction. Together, these results provide the first evidence that AT(2) receptors mediate vasc ular mass regression by stimulating SMC apoptosis in vivo, an effect seen d uring AT(1) receptor blockade but not during converting-enzyme inhibition.