AOS predisposes patients to aggressive and widespread cardiovascular disease and is associated with high mortality. Dissections can occur at relatively mildly increased aortic diameters; therefore, early elective repair of the ascending aorta should be considered. Moreover, cerebrovascular abnormalities were encountered in most patients.

Abstract-Because angiotensin (Ang) metabolites mediate functions independent of Ang II, we investigated their effects on coronary flow in spontaneously hypertensive rats (SHRs). Results were compared with those in the iliac artery and abdominal aorta and the coronary circulation of the Wistar rat. Ang II, III, and IV decreased coronary flow in SHRs and Wistar rats, with Ang III and IV being Ϸ10 and Ϸ1000 times less potent than Ang II. Ang-(1-7) decreased coronary flow at concentrations Ͼ1 mol/L in SHRs. The Ang II type 1 receptor antagonist irbesartan blocked the effects of Ang II, III, and IV, whereas the Ang II type 2 receptor antagonist PD123319 blocked the effects of Ang-(1-7 Key Words: angiotensin III Ⅲ angiotensin (1-7) Ⅲ AT 2 receptor Ⅲ spontaneously hypertensive rat Ⅲ Wistar rat A ngiotensin (Ang) I and II are metabolized by a whole range of peptidases, 1 resulting in the generation of Ang III, Ang IV, and Ang-(1-7). Ang II exerts its effects via Ang II type 1 (AT 1 ) and type 2 (AT 2 ) receptors, whereas Ang III, Ang IV, and Ang-(1-7) mediate functions of their own by stimulating AT 1 , AT 2 , and/or newly discovered receptors. [2][3][4][5][6][7] For instance, Ang III appears to be the preferred agonist of the AT 2 receptor both in the heart and kidney, inducing, respectively, coronary vasodilation 8 and natriuresis. 5 In addition, Ang III regulates blood pressure via central AT 1 receptor activation. 9 Ang IV mediates relaxant effects via Ang II type 4 receptors, 10 whereas Ang-(1-7) activates vasodilatory Mas receptors. 11 AT 2 receptor upregulation and/or AT 1 receptor downregulation (resulting in a relative AT 2 receptor upregulation) is generally believed to induce protective effects under pathophysiological conditions. 12-14 However, such beneficial effects have not been found consistently by all of the investigators. For instance, AT 2 receptors mediate constriction in the renal medulla of 2-kidney, 1-clip rats 15 and in mesenteric arteries of spontaneously hypertensive rats (SHRs), 16 and the AT 2 receptor-induced natriuresis by Ang III no longer occurs in SHRs. 17 Interestingly, blood pressure-lowering in SHRs restored the vasodilatory function of the AT 2 receptor. 18 Chronic treatment of apolipoprotein E knockout mice with Ang IV reversed vascular dysfunction, possibly by enhancing NO bioavailability in an AT 2 and/or Ang II type 4 receptor-dependent manner. 7 Finally, Ang-(1-7) exerts vasodepressor 19,20 and antiremodeling 21 effects under pathological conditions. Although this has been attributed to its capacity to activate Mas receptors, 22 it may also involve AT 2 receptor activation, 20 ACE inhibition, 23 and/or AT 1 receptor blockade. 8,24 Given the conflicting data regarding the endogenous agonist and effect(s) of the AT 2 receptor under pathophysiological conditions, here we compared the effects of Ang II, Ang III, Ang IV, and Ang-(1-7) in the coronary vascular bed, iliac artery, and aorta of the SHR under carefully standardized conditions, both with and without blockade of AT 1 or AT...

Medial degeneration is a key feature of aneurysm disease and aortic dissection. In a murine aneurysm model we investigated the structural and functional characteristics of aortic wall degeneration in adult fibulin-4 deficient mice and the potential therapeutic role of the angiotensin (Ang) II type 1 (AT1) receptor antagonist losartan in preventing aortic media degeneration. Adult mice with 2-fold (heterozygous Fibulin-4+/R) and 4-fold (homozygous Fibulin-4R/R) reduced expression of fibulin-4 displayed the histological features of cystic media degeneration as found in patients with aneurysm or dissection, including elastin fiber fragmentation, loss of smooth muscle cells, and deposition of ground substance in the extracellular matrix of the aortic media. The aortic contractile capacity, determined by isometric force measurements, was diminished, and was associated with dysregulation of contractile genes as shown by aortic transcriptome analysis. These structural and functional alterations were accompanied by upregulation of TGF-β signaling in aortas from fibulin-4 deficient mice, as identified by genome-scaled network analysis as well as by immunohistochemical staining for phosphorylated Smad2, an intracellular mediator of TGF-β. Tissue levels of Ang II, a regulator of TGF-β signaling, were increased. Prenatal treatment with the AT1 receptor antagonist losartan, which blunts TGF-β signaling, prevented elastic fiber fragmentation in the aortic media of newborn Fibulin-4R/R mice. Postnatal losartan treatment reduced haemodynamic stress and improved lifespan of homozygous knockdown fibulin-4 animals, but did not affect aortic vessel wall structure. In conclusion, the AT1 receptor blocker losartan can prevent aortic media degeneration in a non-Marfan syndrome aneurysm mouse model. In established aortic aneurysms, losartan does not affect aortic architecture, but does improve survival. These findings may extend the potential therapeutic application of inhibitors of the renin-angiotensin system to the preventive treatment of aneurysm disease.