(Hypertension. 1999;34:950-957.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Antiproliferative Actions of Angiotensin-(1-7) in Vascular Smooth Muscle
From the Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, NC.
Correspondence to E. Ann Tallant, PhD, The Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1032. E-mail atallant{at}wfubmc.edu
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Abstract |
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 Top Abstract Regulation of Vascular GrowthAng-(1-7) Is a Novel...Antitrophic Actions of Ang-(1-7)Reduction of Neointimal...What Receptor Is Activated...Concluding RemarksReferences |
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Abstract—Hemodynamic factors, circulating hormones, paracrine factors, and intracrine factors influence vascular smooth muscle growth and plasticity. The well-characterized role of angiotensin II in the modulation of vascular tone and cell function may be critically involved in the mechanisms by which vascular smooth muscle responds to signals associated with vascular endothelial dysfunction and increases in oxidative stress. Studies from this laboratory suggest that the trophic actions of angiotensin II may be intrinsically regulated by angiotensin-(1-7), a separate product of the angiotensin system derived from the common substrate, angiotensin I. Exposure of cultured vascular smooth muscle cells to angiotensin-(1-7) inhibited the trophic actions of angiotensin II and reduced the expression of the mitogenic effects of both normal serum and platelet-derived growth factor. The growth-inhibitory actions of angiotensin-(1-7) were blocked by the selective D-alanine7-angiotensin-(1-7) antagonist and the nonselective angiotensin receptor blocker sarcosine1-threonine8-angiotensin II. In contrast, subtype-selective antagonists for the AT1 and AT2 receptors had no effect on the inhibitory actions of angiotensin-(1-7), a finding that is consistent with the pharmacological characterization of a high-affinity 125I-labeled angiotensin-(1-7) binding site in the vasculature by use of selective and nonselective angiotensin II receptor antagonists. The relevance of these findings to the proliferative response of vascular smooth muscle cells after endothelial injury was confirmed by assessment of the effect of a 12-day infusion of angiotensin-(1-7) on neointimal formation. In these experiments, the proliferative response produced by injuring the carotid artery was inhibited by angiotensin-(1-7) through a mechanism that could not be explained by changes in arterial pressure. Because plasma angiotensin-(1-7) increased to levels comparable to those found in animals and human subjects given therapeutic doses of angiotensin-converting enzyme inhibitors, angiotensin-(1-7) may be one factor participating in the reversal of vascular proliferation during inhibition of angiotensin II formation or activity.
Key Words: angiotensin-(1-7) • angiotensin II • muscle, smooth • vascular injury • vascular proliferation • hyperplasia
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Regulation of Vascular Growth |
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TopAbstractRegulation of Vascular GrowthAng-(1-7) Is a Novel...Antitrophic Actions of Ang-(1-7)Reduction of Neointimal...What Receptor Is Activated...Concluding RemarksReferences |
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Regulation of vascular tone is critical to the maintenance of vascular perfusion pressure and blood flow. Within the vessel wall, endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and elements of the cellular matrix (fibroblasts) interact with each other through the local production of autocrine, paracrine, and intracrine factors. Vascular cells both sense and adapt to hemodynamic factors to signal appropriate changes in growth and contractility and determine the adaptive response of the vessel to chronic elevations in arterial pressure. Vascular wall restructuring is a dynamic process that is characterized by hypertrophy and hyperplasia of VSMCs as well as loss of arterial elasticity due to disruption of the balance between the production and degradation of extracellular matrix proteins.1 2 The regulation of vascular growth is thus a key element influencing arterial compliance, distensibility, and resistive changes that occur when luminal pressure is elevated or the vascular wall intima is disrupted.
VSMC growth is stimulated by factors produced by neighboring ECs; released from circulating platelets, neutrophils, and monocytes; and secreted by fibroblasts and VSMCs in an autocrine fashion. Factors that promote vascular growth include platelet-derived growth factor (PDGF), basic fibroblast growth factor, angiotensin II (Ang II), and endothelin.1 2 3 4 The mitogenic actions of Ang II may play an important role in vascular proliferation, because inhibition of its formation or activity attenuates neointimal formation after balloon injury of rat arteries.5 6 Daemen et al7 showed that Ang II infusions into rats markedly stimulated DNA synthesis in both neointimal and medial smooth muscle cells. Su et al8 recently reported that the Ang II–induced proliferative effects were independent of the Ang II–induced pressor response.
In contrast, atrial natriuretic factor (ANF), prostacyclin, prostaglandin (PG) E2, PGE1, PGD2, and nitric oxide (NO) inhibit the growth of cultured VSMCs.9 10 11 12 13 14 15 ANF inhibited the growth of cultured VSMCs through stimulation of guanylate cyclase and the production of cGMP.9 10 Overexpression of prostacyclin synthase in rat VSMCs increased prostacyclin production and decreased DNA synthesis in response to stimulation by serum.16 Pharmacological agents that increase the intracellular concentration of cAMP or cGMP (membrane-permeant cyclic nucleotide analogues, forskolin, or phosphodiesterase inhibitors) reduced serum-stimulated growth of rabbit and rat VSMCs.17 18 Collectively, these results suggest that ANF, NO, and prostaglandins inhibit VSMC growth through an increase in the cellular content of cyclic nucleotides.
The number of factors that may modulate or antagonize the proliferative effects of Ang II was enriched by the discovery that the N-terminal heptapeptide angiotensin-(1-7) [Ang-(1-7)] acts as an antitrophic agent.19 20 These observations are important, because they indicate that the renin-angiotensin system has evolved a mechanism to intrinsically control the agonistic actions of Ang II on both short- and long-term regulation of arterial pressure and vascular growth. Because Ang II stimulates the release of arachidonic acid–derived autacoids and modulates the activity of NO and bradykinin, Ang-(1-7) may be a link to explain the multilevel interaction between proliferative and antiproliferative signal transduction systems. This review describes our continuing investigation of the role of Ang-(1-7) in the regulation of arterial pressure and vascular wall function.
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Ang-(1-7) Is a Novel Hormone of the Renin-Angiotensin System |
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TopAbstractRegulation of Vascular GrowthAng-(1-7) Is a Novel...Antitrophic Actions of Ang-(1-7)Reduction of Neointimal...What Receptor Is Activated...Concluding RemarksReferences |
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Past experiments demonstrated that Ang-(1-7) opposes the actions of Ang II (as recently reviewed21 ). Ang-(1-7), which circulates in blood at concentrations similar to those of Ang II,22 23 rises after inhibition of either angiotensin-converting enzyme (ACE) or long-term administration of AT1 receptor blockers.23 24 25 26 27 Ang-(1-7) is derived from Ang I and Ang II by tissue peptidases, including neprilysin, thimet oligopeptidase, and prolyl endopeptidase.28 29 30 31 The elevation in plasma Ang-(1-7) in response to ACE inhibitor treatment is suppressed by blocking the activity of neprilysin with ecadotril, demonstrating that neprilysin is responsible for the generation of circulating Ang-(1-7).32 Ang-(1-7) is also a substrate for ACE,33 suggesting that ACE inhibition increases Ang-(1-7) not only by blocking Ang II formation but also by preventing Ang-(1-7) degradation. In keeping with this interpretation, the administration of a selective Ang-(1-7) monoclonal antibody or inhibition of Ang-(1-7) formation reverses the antihypertensive effect produced by 9-day administration of lisinopril and losartan in spontaneously hypertensive rats (SHR).34 35 The combination therapy or lisinopril alone also causes a large increase in the circulating half-life of Ang-(1-7),36 further demonstrating that ACE is directly involved in the degradation of the heptapeptide.
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Antitrophic Actions of Ang-(1-7) |
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TopAbstractRegulation of Vascular GrowthAng-(1-7) Is a Novel...Antitrophic Actions of Ang-(1-7)Reduction of Neointimal...What Receptor Is Activated...Concluding RemarksReferences |
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Because Ang-(1-7) releases prostaglandins—both PGI2 and PGE2—from VSMCs,37 38 Ang-(1-7) may participate in or be the initiating factor leading to the antiproliferative effects of these autacoids. We measured the effect of Ang-(1-7) on the incorporation of [3H]thymidine into VSMCs obtained from the aorta of Sprague-Dawley rats to determine whether Ang-(1-7) inhibits vascular growth. The amount of [3H]thymidine incorporation was significantly increased by incubation with either fetal bovine serum (FBS), PDGF, or Ang II. After a 48-hour treatment with 1 µmol/L Ang-(1-7), the incorporation of [3H]thymidine in response to FBS, PDGF, and Ang II was markedly attenuated (to 66.4%, 84.3%, and 75.8% of mitogen-stimulated activity, respectively).19 The reduction in serum-stimulated thymidine incorporation by Ang-(1-7) was dose-dependent, with a peak effect at a dose of 1 µmol/L (Figure 1). Higher concentrations of Ang-(1-7) had no further effect. At the 10-nmol/L dose of Ang-(1-7), thymidine incorporation was inhibited by 25%, whereas the EC50 for inhibition of serum-stimulated VSMC growth was 115 nmol/L. Maximal inhibition by 1 µmol/L Ang-(1-7) was
40% of the response to 1% FBS, which is similar to the growth
inhibition previously reported for ANF.10 Total cell
number in response to treatment with Ang-(1-7) was also determined with
a Coulter counter. The number of cells per well increased to 142% of
basal after treatment with 1% serum, as shown in Figure 1.
Treatment of serum-stimulated cells with 1 µmol/L Ang-(1-7)
significantly reduced the number of cells per well (to 109% of basal).
By comparison, Ang II caused a dose-dependent increase in
[3H]thymidine incorporation, with a maximal
increase of 314% above basal with 1 µmol/L Ang II, and
increased the number of cells per well to 145% of basal
values.19
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It is possible that the EC50 for Ang-(1-7) determined in these experiments is much higher than the actual concentration required to induce antimitogenic effects. This interpretation is based on the finding that 125I-Ang-(1-7) incubated with cultured cells was rapidly degraded to free tyrosine, Val-Tyr, or Ang-(3–7) with only 15% of the initial 125I-Ang-(1-7) remaining intact after a 90-minute incubation.39 These data are consistent with the in vivo findings of a half-life of 9 seconds for Ang-(1-7), which is 1/6 that of Ang II in the circulation.40 Abell et al9 reported a similar rapid degradation of the growth-inhibitory peptide ANF in VSMCs. These data suggest that the antitrophic effects of Ang-(1-7) in VSMCs may be underestimated by its rapid metabolism in intact cells. The antitrophic effects of Ang-(1–7) may, in fact, be due to metabolic fragments of the heptapeptide.
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Reduction of Neointimal Formation by Ang-(1-7) After Vascular Injury |
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TopAbstractRegulation of Vascular GrowthAng-(1-7) Is a Novel...Antitrophic Actions of Ang-(1-7)Reduction of Neointimal...What Receptor Is Activated...Concluding RemarksReferences |
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Ang II infusion into rats markedly stimulated DNA synthesis in both neointimal and medial smooth muscle cells in a normal carotid artery.7 8 Treatment of rats with ACE inhibitors to prevent Ang II formation or AT1 receptor antagonists to block Ang II cellular effects inhibited neointimal formation and medial remodeling after vascular injury.5 6 Thus, Ang II increases vascular growth in vivo, in agreement with its stimulation of thymidine uptake and cell number in cultured VSMCs. Because Ang II and Ang-(1-7) have opposite effects on VSMC growth, we determined the effect of Ang-(1-7) on medial and neointimal proliferation stimulated by balloon catheter injury to the rat carotid artery. Intravenous infusion of Ang-(1-7) with a chronically implanted minipump (24 µg · kg-1 · h-1 at a rate of 5 µL/h for 12 days) increased the plasma Ang-(1-7) concentration to 166±41.2 fmol/mL (n=6) from 46.9±11 fmol/mL (n=8) in carotid artery–injured rats infused with saline. Plasma concentrations of Ang II (27.3±7.6 compared with 27±11.0 fmol/mL), diastolic and systolic pressures, and heart rate were similar in rats infused with Ang-(1-7) or saline,20 in agreement with our previous studies.41
Histological examination of carotid artery cross sections showed that balloon-catheter injury resulted in the formation of a neointima in both the saline- and Ang-(1-7)–infused rats, as shown in Figure 2. Morphometric analysis indicated that Ang-(1-7) infusion had no effect on the medial area of the injured or the contralateral uninjured artery compared with saline controls (Figure 3). In contrast, Ang-(1-7) infusion significantly reduced the neointimal area compared with rats infused with saline (0.10±0.009 versus 0.063±0.011 mm2, n=6 to 8, P<0.05). Thus, exogenous Ang-(1-7) infusion reduced neointimal formation after vascular injury. Most importantly, the effects of Ang-(1-7) on the vasculature occurred in the absence of changes in blood pressure and at concentrations of the peptide only 2-fold higher than in saline-treated rats.
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In previous studies, we showed that infusions of Ang-(1-7) at the same concentration increased urinary prostaglandin excretion.41 Thus, one potential mechanism for our observations in the injured carotid artery is that Ang-(1-7) stimulated prostaglandin production to inhibit vascular proliferation. Ang-(1-7) increased prostaglandin formation in rat,38 porcine,37 and rabbit42 VSMCs. Consistent with this, infusion of prostacyclin analogues was antiproliferative after vascular injury.43 Because prostacyclin receptors on VSMCs activated adenylate cyclase to produce cAMP44 and compounds that increased the intracellular concentration of cAMP reduced mitogen-activated protein kinase activity in VSMCs and fibroblasts,45 Ang-(1-7) may inhibit growth by stimulating prostacyclin production, increasing cellular cAMP, and reducing mitogen-activated protein kinase activity. Furthermore, the vasodilation of pial arteries by Ang-(1-7) and the depressor component of the response to Ang-(1-7) in the pithed rat were reduced by prior treatment with the cyclooxygenase inhibitor indomethacin, indicating that these hemodynamic responses to Ang-(1-7) were also mediated by prostaglandins.46 47 Thus, an increase in prostacyclin production in response to Ang-(1-7) may mediate both the antihypertensive and antitrophic effect of the peptide.
Our results suggest that the signal transduction mechanism for the antiproliferative effects of Ang-(1-7) entail liberation of prostacyclin through an AT(1-7) receptor–mediated event. Muthalif et al42 reported that Ang-(1-7) activated a cytosolic phospholipase A2 (cPLA2) in rabbit VSMCs to release arachidonic acid. We showed that the Ang-(1-7)–mediated release of prostaglandins occurs via a pathway that involves no changes in cellular inositol phosphate concentrations or mobilization of intracellular calcium.37 48 49 Thus, Ang-(1-7) may also activate a calcium-independent PLA2 to release arachidonic acid for prostacyclin production. Alternatively, the heptapeptide may be operating on a receptor subtype that is either linked to activation of a potassium channel50 or may stimulate the secondary release of kinin. In this context, studies by us51 and others31 showed that Ang-(1-7) augments the vasodepressor actions of bradykinin. This action may be related in part to the observation that Ang-(1-7) functions as an endogenous inhibitor of the C-terminal domain of somatic ACE. We confirmed this finding, first demonstrated by use of isolated somatic ACE,33 in intact normal and hypertensive rats.36 It is evident that further studies are necessary to dissect the signal transduction pathway that is activated by Ang-(1-7). Studies in this direction may uncover important intracellular sites regulating the interplay between second messenger molecules and kinases in the regulation of trophic functions.
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What Receptor Is Activated by Ang-(1-7)? |
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TopAbstractRegulation of Vascular GrowthAng-(1-7) Is a Novel...Antitrophic Actions of Ang-(1-7)Reduction of Neointimal...What Receptor Is Activated...Concluding RemarksReferences |
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Although the majority of vascular responses to Ang II are mediated by the AT1 receptor,3 4 several studies suggest that stimulation of the AT2 receptor attenuates vascular growth through the release of cGMP.52 53 54 However, the antiproliferative effects of Ang-(1-7) cannot be explained by the activation of an AT2 receptor by Ang-(1-7). Attenuation of thymidine incorporation by Ang-(1-7) in the presence of 1% FBS was unaffected by antagonists selective for AT1 (L158,809) or AT2 (PD123177) receptors (Figure 4A, left). It is unlikely that the inability of PD123177 to block the antiproliferative effects of Ang-(1-7) is the result of incomplete AT2 receptor blockade, because the antagonist was used at a concentration of 10 µmol/L, a concentration sufficient to block AT2-mediated events. In contrast, a 10-µmol/L concentration of the sarcosine derivative of Ang II ([Sar1-Thr8]-Ang II, Sarthran) completely blocked growth inhibition by Ang-(1-7), which indicates that the effect of the heptapeptide was a result of the activation of an angiotensin receptor pharmacologically distinct from either AT1 or AT2 receptors.
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Recently, we studied the effect of the Ang-(1-7)–selective antagonist [D-Ala7]-Ang-(1-7) on the antiproliferative response to Ang-(1-7). [D-Ala7]-Ang-(1-7) is a modified form of Ang-(1-7) in which proline at position 7 is replaced with D-alanine. This amino acid substitution results in a molecule that has no agonistic activity,55 although it selectively blocks hemodynamic and renal responses to Ang-(1-7). Moreover, [D-Ala7]-Ang-(1-7) did not compete for binding of 125I-Ang II to rat adrenal AT1 or AT2 receptors.55 [D-Ala7]-Ang-(1-7) competed for 125I-Ang-(1-7) binding to bovine aortic ECs (BAECs) with high affinity.56 The addition of 10 µmol/L [D-Ala7]-Ang-(1-7) to VSMCs pretreated with 0.5% FBS blocked the growth-inhibitory response to 1 µmol/L Ang-(1-7), as shown in Figure 4A, right. These data indicate that Ang-(1-7) inhibits VSMC growth through activation of a non-AT1, non-AT2 receptor that is sensitive to either [Sar1-Thr8]-Ang II or [D-Ala7]-Ang-(1-7).
Ang II stimulation of [3H]thymidine incorporation was attenuated by the AT1-selective antagonists losartan and L158,809, whereas the AT2 antagonist PD123177 was ineffective (Figure 4B), confirming that the AT1 receptor mediates the mitogenic response to Ang II. However, addition of Ang II to VSMCs in the presence of the AT1 antagonist losartan or L158,809 caused a significant reduction in the incorporation of [3H]thymidine compared with the unstimulated control (to 71.0% and 60.5% of basal, respectively). Micromolar concentrations of the AT2 antagonist PD123319 blocked Ang II–mediated inhibition of the proliferation of ECs,52 VSMCs transfected with the AT2 receptor,53 and VSMCs from embryonic or neonatal rats.54 These findings suggest that the Ang II–mediated inhibition of VSMC growth that we observed in VSMCs from adult rats might also be mediated by an AT2 receptor. However, if Ang II inhibited [3H]thymidine incorporation in VSMCs from adult rats through activation of an AT2 receptor, then thymidine incorporation would be increased when AT2 receptors were blocked, as observed in endothelial cells52 and VSMCs transfected with the AT2 receptor.53 We did not observe an increase in [3H]thymidine incorporation in the presence of Ang II and 10 µmol/L PD123177 or CGP42112A (Figure 3B). Furthermore, high concentrations of CGP42112A have agonistic properties at some AT2 receptors; 10 µmol/L CGP42112A reduced thymidine incorporation and potentiated the antimitogenic properties of Ang II in rat coronary ECs.52 We did not observe an agonistic effect of CGP42112A in adult rat VSMCs or a potentiation of the response to Ang II, suggesting that Ang II did not inhibit vascular growth through activation of an AT2 receptor in adult VSMCs. Thus, we hypothesize that Ang II inhibited growth of VSMCs from adult rats through activation of a non-AT1, non-AT2 receptor when AT1 receptors are blocked. Because Ang II competed for 125I-Ang-(1-7) binding to BAECs, albeit with a lower affinity than Ang-(1-7),56 Ang II may inhibit growth of losartan-treated VSMCs through activation of the non-AT1, non-AT2 receptor that is activated by Ang-(1-7). Consistent with this interpretation is the possibility that Ang II may be rapidly converted into Ang-(1-7) in experiments using cultured cells. We previously showed the presence of Ang-(1-7)-forming enzymes in ECs and VSMCs.29 30 The time of exposure needed to measure a change in the incorporation of thymidine (>30 minutes) is more than sufficient for Ang II to be converted into Ang-(1-7). Further work is clearly required to understand the pharmacological mechanism and receptor subtype at which Ang II is acting when binding to the AT1 receptor is prevented. Furthermore, the potential interactions between the AT2 and AT(1-7) receptors will require a precise definition of alternative receptor mechanisms and a more thorough evaluation of the effects of PD123319 on angiotensin receptors.
Recognition of the physiological responses to Ang-(1-7) occurred concurrently with the identification of subtype-selective ligands for different molecular forms of Ang II receptors. Characterization of physiological or cellular responses to Ang-(1-7) was thus accompanied by attempts to define the receptor subtype mediating these responses. Although some of the characterized responses to Ang-(1-7) were blocked by AT1 or AT2 receptor antagonists,47 48 57 58 59 Ang-(1-7) is a poor competitor at the prototypical AT1 receptor in VSMCs37 38 or the AT2 receptor in differentiated NG108-15 or pancreatic cells.60 61 The majority of responses to Ang-(1-7) were not blocked by an AT1 or AT2 receptor antagonist.37 47 51 62 63 These include release of prostaglandins from C6 glioma cells and porcine endothelial cells,37 62 relaxation of canine coronary artery rings,51 63 and the reduction in blood pressure in the pithed rat.47 These responses were inhibited, however, by [Sar1-Thr8]-Ang II but not by AT1 or AT2 receptor antagonists. In the SHR given a combination of lisinopril and losartan for 9 days to increase Ang-(1-7) concentrations, a pressor response was observed in response to an intravenous infusion of [Sar1-Thr8]-Ang II, an Ang-(1-7) antibody, or an inhibitor of Ang-(1-7) formation (neprilysin).34 35 Pretreatment of these rats with the AT2 antagonist PD123319 had no effect on blood pressure, nor did administration of [Sar1-Thr8]-Ang II after treatment with the Ang-(1-7) antibody. Thus, [Sar1-Thr8]-Ang II reversed the antihypertensive effects of lisinopril and the AT1 antagonist losartan, even in the presence of an AT2 receptor antagonist. These results suggest that Ang-(1-7) activates a novel non-AT1, non-AT2 angiotensin receptor to produce effects that are opposite to those produced by Ang II.
We identified an Ang-(1-7) binding site on BAECs.56 The 125I-Ang-(1-7) binding site on BAECs was competed for by [Sar1-Ile8]-Ang II and [D-Ala7]-Ang-(1-7) but not by losartan or PD123319. A similar 125I-Ang-(1-7) binding site, sensitive to Ang-(1-7) and [D-Ala7]-Ang-(1-7), was visualized on the endothelium of canine coronary artery rings,21 consistent with functional effects of Ang-(1-7) in canine and porcine coronary arteries.51 63 In more recent studies of vessels from rats treated with the combination of lisinopril and losartan for 9 days as described above,34 35 we found evidence of non-AT1, non-AT2 binding in the endothelial layer of the aorta as well as within the smooth muscle and adventitial layers (Figure 5). Using the ligand 125I-[Sar1-Thr8]-Ang II in the presence of micromolar concentrations of losartan and PD123319, we showed that the remaining binding sites were competed for by [D-Ala7]-Ang-(1-7) (Figure 5). Thus, the effects of [D-Ala7]-Ang-(1-7) to selectively block responses to Ang-(1-7) in VSMCs are consistent with the pharmacological characterization of an Ang-(1-7) binding site within the vasculature. We propose that this non-AT1, non-AT2 receptor mediates the antihypertensive and antitrophic effects of Ang-(1-7). We refer to this receptor as the AT(1-7) receptor, in accordance with the guidelines established by the International Union of Pharmacology Nomenclature Subcommittee for Angiotensin Receptors.64 65 The AT(1-7) receptor is defined by its sensitivity to Ang-(1-7), its antagonism by [Sar1-Thr8]-Ang II and [D-Ala7]-Ang-(1-7), and its lack of response, either functional or in competition for binding, to losartan or PD123319, as shown in the Table.
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Concluding Remarks |
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TopAbstractRegulation of Vascular GrowthAng-(1-7) Is a Novel...Antitrophic Actions of Ang-(1-7)Reduction of Neointimal...What Receptor Is Activated...Concluding RemarksReferences |
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Vascular growth is regulated by a balance between proliferative and antiproliferative factors. Two members of the family of angiotensin peptides—Ang II and Ang-(1-7)—oppose each other in regulating vascular growth. Ang II is clearly mitogenic in cultured VSMCs as well as in intact arteries in the absence of hemodynamic changes. In contrast, Ang-(1-7) inhibits stimulated growth of VSMCs and reduced neointimal formation at concentrations of the peptide only 2-fold higher than in saline-treated rats and in the absence of changes in blood pressure. A balance between the tissue concentrations of Ang II and Ang-(1-7) is thus critical in the long-term maintenance of vessel structure.
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Acknowledgments |
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This work was supported in part by grants HL-51952 and HL-56973 from the National Institutes of Health, Bethesda, Md, and a Grant-in-Aid from the North Carolina Affiliate of the American Heart Association.
Received June 22, 1999; first decision July 23, 1999; accepted August 2, 1999.
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TopAbstractRegulation of Vascular GrowthAng-(1-7) Is a Novel...Antitrophic Actions of Ang-(1-7)Reduction of Neointimal...What Receptor Is Activated...Concluding RemarksReferences |
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