No abstract

No abstract

When increased in vascular tissues, angiotensin-converting enzyme 2 (ACE2), a carboxypeptidase that hydrolyzes angiotensin II to angiotensin-(1-7), may augment the growth inhibitory and vasodilatory effects of the heptapeptide. We investigated the regulation of ACE2 and angiotensin-(1-7) expression in aortas and carotid arteries of 12-wk-old male spontaneously hypertensive rats (SHR) by determining the effect of sustained angiotensin type 1 (AT 1) receptor blockade with olmesartan (10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 , n ϭ 13) compared with those that received atenolol (30 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 , n ϭ 13), hydralazine (10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 , n ϭ 13), or vehicle (n ϭ 21). Systolic blood pressures were ϳ30% lower (P Ͻ 0.05) in rats treated for 2 wk with olmesartan compared with vehicletreated rats. Both atenolol and hydralazine produced similar decreases in systolic blood pressure. ACE2 mRNA in the thoracic aorta of olmesartan-treated rats (n ϭ 8) was fivefold greater (P Ͻ 0.05) than that in vehicle-treated rats (n ϭ 16), whereas atenolol (n ϭ 8) or hydralazine (n ϭ 8) had no effect. Immunostaining intensities in rats treated with olmesartan (n ϭ 5) were also associated with increased (P Ͻ 0.05) ACE2 and angiotensin-(1-7) in thoracic aorta media compared with vehicle-treated rats. In contrast, immunostaining intensities for both ACE2 and angiotensin-(1-7) were not different from vehicle (n ϭ 5) in carotid arteries of SHR medicated with either atenolol (n ϭ 5) or hydralazine (n ϭ 5). A comparison of vessel wall dimensions showed that olmesartan selectively reduced the thoracic aorta media-to-lumen ratio (P Ͻ 0.05) and media thickness (P Ͻ 0.05) without an effect on carotid artery morphometry. Compared with vehicle-treated SHR, vascular hypertrophy determined from media and lumen measurements was not changed in SHR given either atenolol or hydralazine. These data represent the first report of ACE2 and angiotensin-(1-7) expression in the aorta and carotid arteries of SHR. Increased ACE2 and angiotensin-(1-7) in association with altered dimensions of the thoracic aorta but not carotid arteries in response to olmesartan treatment provides evidence that this pathway is regulated by AT1 receptors and may be important in mediating the pressure-independent vascular remodeling effects of angiotensin peptides.angiotensin-converting enzyme 2; angiotensin type 1 receptor; vascular remodeling ANGIOTENSIN-CONVERTING ENZYME (ACE)2 is a newly recognized ACE homolog within the renin-angiotensin system (RAS) that is produced and secreted from a variety of cell types (19). Although ACE2 may act on several substrates, it exhibits high catalytic efficiency specifically for the hydrolysis of ANG II into the vasodilator and growth inhibitor heptapeptide angiotensin-(1-7) [ANG-(1-7)] (7, 13, 15). In previous experiments, we showed that ANG-(1-7) mediates the vasodilator effects of combined ACE inhibition and angiotensin type 1 (AT 1 ) receptor blockade (22). Furthermore, a continuous intravenous infusion of ANG-(1-7) reduced neointimal growth in caroti...

This study demonstrates for the first time an antiatherogenic effect of AT(1) receptor blockade in nonhuman primates. Losartan inhibited fatty-streak formation through mechanisms that may include protection of LDL from oxidation and suppression of vascular monocyte activation and recruitment factors.

Abstract-Regulation of vascular smooth muscle cell growth is critical to the maintenance of normal blood flow and vessel patency. Angiotensin-(1-7) [Ang-(1-7)] inhibits proliferation of vascular smooth muscle cells in vitro and opposes the mitogenic effects of angiotensin II. The present study investigated whether Ang-(1-7) inhibits vascular smooth muscle cell growth in vivo by determining its effect on neointimal formation and medial remodeling in balloon-injured carotid arteries. The carotid arteries of adult male Sprague-Dawley rats were injured with a balloon embolectomy catheter. Ang-(1-7) in saline (24 g/kg per hour) or saline alone was infused intravenously for 12 days after injury. Pumps containing bromodeoxyuridine were implanted at the same time to determine DNA synthesis. Intravenous infusion increased plasma Ang-(1-7) to 166.0Ϯ41.2 fmol/mL (nϭ6) compared with 46.9Ϯ4.2 fmol/mL (nϭ8) in saline-infused rats. Plasma concentrations of Ang II were not changed by Ang-(1-7) infusion. Elevation in circulating Ang-(1-7) had no effect on either blood pressure or heart rate compared with saline controls. Histomorphometric analysis of carotid arteries indicated that Ang-(1-7) infusion significantly reduced neointimal area compared with rats infused with saline (0.063Ϯ0.011 versus 0.100Ϯ0.009 mm 2 ; PϽ0.05). In contrast, Ang-(1-7) infusion had no effect on medial area of the injured or the contralateral uninjured artery compared with saline controls. Ang-(1-7) infusion also reduced the rate of DNA synthesis in both the neointima and the media of the injured vessels. Therefore, exogenous Ang-(1-7) inhibited vascular smooth muscle cell proliferation associated with balloon-catheter injury. Similar increases in endogenous plasma Ang-(1-7) and inhibition of neointimal growth were observed in rats after angiotensin-converting enzyme inhibitor or angiotensin type 1 receptor antagonist administration, suggesting that Ang-(1-7) may contribute to the in vivo antiproliferative effects of these agents on vascular smooth muscle.

SummaryThe existence of a bone marrow renin-angiotensin system (RAS) is evidenced by the association of renin, angiotensin converting enzyme (ACE), and angiotensin (Ang) II and its AT 1 and AT 2 receptors with both normal and disturbed haematopoiesis. The expression of RAS components by rat unfractionated bone marrow cells (BMC), haematopoietic-lineage BMC and cultured marrow stromal cells (MSC) was investigated to determine which specific cell types may contribute to a local bone marrow RAS. The mRNAs for angiotensinogen, renin, ACE, and AT 1a and AT 2 receptors were present in BMC and in cultured MSC; ACE2 mRNA was detected only in BMC. Two-colour flow fluorocytometry analysis showed immunodetectable angiotensinogen, ACE, AT 1 and AT 2 receptors, and Ang II, as well as binding of Ang II to AT 1 and AT 2 receptors, in CD4 + , CD11b/c + , CD45R + and CD90 + BMC and cultured MSC; renin was found in all cell types with the exception of CD4 + BMC. Furthermore, Ang II was detected by radioimmunoassay in MSC homogenates as well as conditioned culture medium. The presence of Ang II receptors in both haematopoietic-lineage BMC and MSC, and the de novo synthesis of Ang II by MSC suggest a potential autocrine-paracrine mechanism for local RAS-mediated regulation of haematopoiesis.

The current study was designed to evaluate the effects of a disrupted social environment on the endothelial integrity of various vascular segments in male cynomolgus monkeys (Macaca fascicularis). Each of 20 single-caged adult monkeys was fed a diet comparable to a person's ingestion of 240 mg cholesterol/day for a 10-week baseline period and then was introduced as a stranger into a four-member social group for 3 days. Half of the monkeys received a f-adrenergic blocking agent (metoprolol) via subcutaneous implant 2 days before and during group housing. The social manipulation produced persistent sympathetic arousal as evidenced by significantly elevated heart rates among untreated monkeys (p<0.01) but not among their metoprolol-treated counterparts, whose heart rate declined (p<0.05). After the social manipulation, all monkeys were necropsied and evaluated for endothelial incorporation of immunoglobulin G (as an indicator of cell death), endothelial cell replication, the presence of adherent leukocytes, and arterial low density lipoprotein permeability and concentration. At branching sites in the thoracic aorta, immunoglobulin G incorporation and endothelial cell replication were significantly greater in untreated monkeys than in metoprolol-treated monkeys (p<0.01 for both analyses); no differences existed at nonbranch sites. Endothelial cell replication in the coronary arteries (where immunoglobulin G incorporation was not examined) was also greater among untreated than among metoprolol-treated monkeys. No significant differences were observed between treatment groups in arterial low density lipoprotein permeability or leukocyte adherence; estimates of arterial low density lipoprotein concentrations were higher among untreated than among metoprolol-treated monkeys, but only in the abdominal portion of the aorta. These results indicate that social disruption is associated with both sympathetic nervous system arousal and indexes of endothelial dysfunction, effects that may be prevented by treatment with a .8-adrenergic blocking agent. (Circulation Research 1991;68:1270-1279 T here is increasing evidence that psychosocial factors contribute to the development of atherosclerosis.' In experimental studies of cholesterol-fed cynomolgus monkeys (Macaca fascicularis), for instance, we2 have previously demonstrated that chronic exposure to stress (repeated disruption of social group memberships) potentiates coronary artery atherogenesis among animals of high Supported, in part, by grants from the National Heart, Lung, and Blood Institute (HL-14164, HL-26551, and HL-40962)

Angiotensin converting enzyme 2 (ACE2) is a key enzyme of the renin-angiotensin system (RAS) that influences the relative expression of angiotensin (Ang) II and Ang-(1–7). Although ACE2 expression increases in normal pregnancy, the impact of ACE2 deficiency in pregnancy has not been elucidated. We determined the influence of ACE2 deficiency on circulating and tissue RAS components, fetal and maternal growth characteristics, and maternal hemodynamics (mean blood pressure (MBP) and cardiac output (CO)) at day 18 of gestation. Gestational body weight gain was lower in the ACE2 knock out (KO) vs C57BL/6 (WT) mice (30.3 ± 4.7 vs 38.2 ± 1.0 g, p<0.001). Fetal weight (0.94 ± 0.1 vs 1.24 ± 0.01 g, p<0.01) and length (19.6 ± 0.2 vs 22.2 ± 0.2 mm, p<0.001) were less in KO. MBP was significantly reduced in WT with pregnancy; it was elevated (p<0.05) in the KO virgin and pregnant mice, and this was associated with an increased CO in both WT and KO pregnant mice (p<0.05). Plasma Ang-(1–7) was reduced in pregnant KO mice (p<0.05). Placenta Ang II levels were higher in KO mice (52.9 ± 6.0 vs 22.0 ± 3.3 fmol/mg protein, p<0.001). Renal Ang II levels were greater in KO virgin mice (30.0 ± 1.7 vs 23.7 ± 1.1 fmol/mg protein, p<0.001). There was no change in the Ang-(1–7) levels in the KO placenta and virgin kidney. These results suggest that ACE2 deficiency and associated elevated placenta Ang II levels impact pregnancy by impairing gestational weight gain and restricting fetal growth.