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

Abstract

Abstract-Angiotensin type 2 (AT 2 ) 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 AT 1 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 AT 2 receptors in this model, spontaneously hypertensive rats were given valsartan, an AT 1 antagonist, or enalapril, in combination or not with the AT 2 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 3 H-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. 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 vascular mass regression by stimulating SMC apoptosis in vivo, an effect seen during AT 1 receptor blockade but not during convertingenzyme inhibition.

AT 2 Receptor-Mediated Relaxation Is Preserved After Long-Term AT 1 Receptor Blockade

“…Although we did not measure Ang II levels in the rats treated with candesartan cilexetil, it would be expected that this treatment would have elevated Ang II levels at least 5-fold. 34 As expected, candesartan cilexetil virtually abolished Ang II-evoked contraction in mesenteric arteries, which is consistent with the prolonged duration of action of this compound, both in vivo 25 and ex vivo. 24 Although it was not expected that AT 1 R blockade would directly affect AT 2 Rmediated responses (because different receptor subtypes), it was not known if increased circulating levels of Ang II could desensitize the action of Ang II at AT 2 Rs, as occurred at AT 1 Rs.…”

From bedside to bench to bedside: role of renin-angiotensin-aldosterone system in remodeling of resistance arteries in hypertension

“…However, an imbalance between growth and apoptosis could be important (128,190). Many studies (27,151,166) have suggested that ACE inhibitors and AT 1 R blockers could contribute to regression of vascular wall growth through activation of proapoptotic pathways. Apoptosis may also play a role in microvascular rarefaction, which has been implicated in the development of hypertension (56).…”

Angiotensin Type 2 Receptor Agonist Compound 21 Reduces Vascular Injury and Myocardial Fibrosis in Stroke-Prone Spontaneously Hypertensive Rats

“…Most well-known effects of Ang II that contribute to unfavorable vascular remodeling and consequent hypertensive complications are mediated via AT 1 R, whereas those exerted via AT 2 R are less well known and appear to counteract many of its effects exerted via AT 1 R. 4,5 AT 2 Rmediated effects seem to exert vasculoprotective actions via vasodilation, NO production, 6 -8 and apoptosis and inhibition of growth and fibrosis. 5,9,10 Beneficial vascular effects of AT 1 R blockade have been at least partially attributed to unopposed AT 2 R stimulation. 7,11,12 …”

“…Most well-known effects of Ang II that contribute to unfavorable vascular remodeling and consequent hypertensive complications are mediated via AT 1 R, whereas those exerted via AT 2 R are less well known and appear to counteract many of its effects exerted via AT 1 R. 4,5 AT 2 Rmediated effects seem to exert vasculoprotective actions via vasodilation, NO production, 6 -8 and apoptosis and inhibition of growth and fibrosis. 5,9,10 Beneficial vascular effects of AT 1 R blockade have been at least partially attributed to unopposed AT 2 R stimulation. 7,11,12 Several studies have suggested beneficial vascular effects of AT 2 R. We reported previously that AT 2 R mediated downregulation of vascular RhoA/Rho kinase/myosin light chain phosphorylation in Ang II and AT 1 R antagonist valsartantreated or AT 2 R partial agonist CGP42112A-treated cultured vascular smooth muscle cells, suggesting a role for vascular AT 2 R in blood pressure (BP) lowering during chronic AT 1 R blockade.…”