(Hypertension. 1996;28:91-97.)
© 1996 American Heart Association, Inc.
Articles |
Angiotensin II Type 2 Receptor mRNA Expression in the Developing Cardiopulmonary System of the Rat
Institut National de la Sante et de la Recherche Medicale (INSERM) U36, and Laboratoire de Medecine Experimentale, College de France, Paris.
Correspondence to Jean-Marie Gasc, INSERM U36, College de France, 3 rue d'Ulm, 75005 Paris, France.
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Abstract |
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Recent studies have shown that angiotensin II has a trophic action on the heart. The presence of two types of angiotensin II receptors, type 1 (AT1) and type 2 (AT2), has been reported in the rat heart. This in situ hybridization study describes the tissue and cell location of AT2 receptor mRNA in the developing rat cardiopulmonary system, from 15 days of gestation to adulthood. Expression of AT1A receptor mRNA was studied in parallel for direct comparison. The aortic arch and pulmonary artery expressed high levels of AT2 receptor mRNA from 15 days of gestation up until 15 days postpartum, whereas expression of this mRNA was observed only just before and after birth in the coronary arteries. AT2 receptor mRNA was not detected in any cardiac muscle of the fetus, neonate, or adult. The annulus of all four heart valves expressed AT2 mRNA from 21 days of gestation until 10 days postpartum, but no labeling was seen in the valve leaflets. The subendocardial atrial tissue showed a high level of AT2 receptor mRNA expression during the early postnatal period, but no expression was observed in the atrial myocytes from fetal stages to adulthood. The bronchi and trachea, but not the lung parenchyma, showed a high level of AT2 receptor mRNA expression starting from 17 days of gestation until 10 days postpartum. AT2 receptor mRNA expression in the cardiopulmonary system is therefore transient, developmentally regulated, and mostly located in vascular structures. By these three characteristics, its expression contrasts with that of AT1A, which is continuously expressed in the cardiac muscle to adulthood. This spatiotemporal pattern of expression of angiotensin II receptor mRNAs during development suggests a possible role for angiotensin II in organogenesis.
Key Words: receptors, angiotensin II • heart • in situ hybridization • gene expression
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Introduction |
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The role of the renin-angiotensin system in cardiac diseases is gaining attention, and the growth-promoting effects of angiotensin II (Ang II), such as induction of cardiac hypertrophy,1 2 3 4 5 are of particular interest. Ang II also exerts direct positive inotropic6 and chronotropic7 effects on the heart. Ang II therefore appears to be an important factor in cardiac physiopathology.
Although the known effects of Ang II on the heart, particularly hypertrophic effects, seem to be mediated via the type 1 (AT1) receptor,4 5 8 9 the presence of type 2 (AT2) receptor in this organ raises the question of its possible role or roles. The presence of AT2 receptors in the heart has previously been shown only by binding studies with specific ligands that allow the distinction of AT1 and AT2 binding sites,3 10 and the presence of AT1A mRNA expression has been shown by reverse transcriptase–polymerase chain reaction.3 11 In the adult rat heart, in situ autoradiographic quantitative binding studies on whole heart sections have revealed a low level of expression of both AT1 and AT2 receptors, with a uniform distribution and approximately equivalent amounts of each receptor type.10 The exclusive presence of AT1 in the rat heart conduction system has also been reported.12 Radioligand binding studies on cultured cells have shown the presence in various proportions of both AT1 and AT2 receptors in cells derived from the fetal, neonatal, and adult rat heart.11 13 14 15 Comparison of studies performed in tissues and cultured cells is difficult because of the different methodologies and experimental conditions used. In addition, none of these studies allows precise identification of the cell types that express the receptors in the heart: In vitro cell cultures do not reproduce the in vivo conditions, and binding studies do not allow precise determination of the target cells for Ang II. Finally, no systematic study has been undertaken to follow the spatiotemporal expression of Ang II receptor subtypes with the same technique.
We undertook the present experiments to describe the distribution and developmental evolution of AT2 receptor mRNA expression in the heart at the cellular level. Sections of rat hearts, including the large blood vessels and respiratory tree, were taken from 15 days of gestation until adulthood, and AT2 mRNA expression was determined by in situ hybridization with a cRNA probe specific for the AT2 receptor. The results are compared with those obtained under identical conditions in the same experiments with an AT1A-specific probe.
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Methods |
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Rat AT2 Receptor cDNA Cloning
Total RNA was extracted from rat adrenal gland by the acid guanidinium isothiocyanate/phenol/chloroform method, and reverse transcriptase–polymerase chain reaction amplification of the full-length AT2 cDNA was performed as described by Shanmugam et al16 with the use of the already published sequence of the rat AT2 receptor cDNA.17 18 The polymerase chain reaction product was gel purified, digested with EcoRI, and subcloned into the vector pBluescript II KS (Stratagene). The sequence of the insert was verified by dideoxy sequencing with a Sequenase kit (United States Biochemical Corp). A clone containing the rat AT2 cDNA sequence that corresponded exactly to that published17 18 was used for the synthesis of cRNA probes.
Synthesis of cRNA Probes
Before transcription, the plasmid containing the AT2 cDNA (1 kb) was linearized with Xba I or HindIII such that noncomplementary (sense) or complementary (antisense) RNA probes could be synthesized in the presence of 35S-UTP (Amersham) with T3 or T7 RNA polymerase, respectively.16 The AT1A antisense probe (2 kb) was similarly synthesized after linearization of a pBluescript II KS containing the AT1A cDNA with Hpa I and transcription with T3 RNA polymerase.19
In Situ Hybridization
All animal experiments were carried out in accordance with institutional guidelines. Pregnant Sprague-Dawley rats (Iffa-Credo; three at each gestational stage studied) were anesthetized with chloroform at 15, 17, 19, and 21 days of gestation (E15, E17, E19, and E21; the day males and females were caged together at 8 AM was considered day 0). The fetuses were removed and fixed intact in 4% buffered (pH 7.6) paraformaldehyde, except in the case of the E21 fetuses, in which the hearts were dissected and fixed as separate organs. Three pregnant rats were allowed to deliver, and pups were killed by decapitation at postnatal days (D) 0 (2 hours after birth), 1, 3, 10, 15, and 22. The heart along with the aorta and pulmonary artery was excised and fixed as described above. The heart and aorta of the adult rat was also dissected and fixed in the same conditions. Coronal and sagittal sections prepared from the heart of 10 different rats at each stage were hybridized with the AT2 antisense and sense cRNA probes as well as with the AT1A antisense probe (see technical details in References 19 and 20).
The results of AT1A and AT2 receptor mRNA expression in the rat fetal, neonatal, and adult heart were first interpreted by film autoradiography and then by emulsion autoradiography. For film autoradiography, the slides were exposed for 5 days at room temperature on X-OMAT AR film (Eastman Kodak). Cellular localization of AT1A and AT2 mRNAs was obtained by emulsion autoradiography after the slides were dipped in Kodak NTB2 liquid emulsion. After 45 days of exposure at 4°C, the autoradiographs were developed and fixed and the slides stained by toluidine blue for microscopic analysis.
Immunostaining
Paraffin sections adjacent to those used for in situ hybridization were immunostained with an antibody to smooth muscle actin (Dako) following a routine technique for immunoperoxidase staining. After deparaffinization, sections received 3% normal horse serum (15 minutes) and then the anti-actin antibody (dilution, 1:300; 90 minutes at room temperature). The secondary antibody was a horse biotinylated antibody to mouse immunoglobulins preabsorbed on rat immunoglobulins (Vector), and the amplification system was the ABC Elite (Vector). Peroxidase activity was detected with diaminobenzidine (DAB) and H2O2 as substrates.
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Results |
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AT2 receptor mRNA distribution was studied in the fetal (E15, E17, E19, and E21), postnatal (D0, D1, D3, D10, D15, and D22), and adult rat heart, blood vessels, trachea, and lung. Tissue sections were also hybridized with an AT1A antisense probe. All results were observed and interpreted macroscopically and microscopically.
Macroscopic Studies
Macroscopic analysis of film autoradiography of a whole E19 fetus (Fig 1
, top row) revealed strong AT2 hybridization signals in the aorta, trachea, and bronchi but not in the heart or lung parenchyma. Other structures that also appeared strongly positive for AT2 mRNA were the adrenal gland, urogenital cord, and subdermal layers of the skin. A weaker hybridization signal was observed in kidney, undifferentiated mesenchymes, axial perichondrium, and diaphragm. At the same age, AT1A mRNA (Fig 1, bottom row) displayed a different pattern of tissue distribution. Specifically, there was weak labeling in the heart and aorta and strong labeling in the lung parenchyma. The other structures labeled with the AT1A probe were the liver, kidney, adrenal gland, and various mesenchymes.
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At E21, the distribution of the receptor mRNAs in the cardiopulmonary system was also strikingly different for AT2 and AT1A (Fig 1
): Large blood vessels, trachea, and bronchi continued to be strongly positive for AT2 mRNA and weakly or not labeled with AT1A, whereas lung parenchyma was negative for AT2 and positive for AT1A. At D0, D3, and D22 (Fig 1), AT2 labeling decreased progressively in all cardiopulmonary structures to reach the level of the sense probe (not shown). In contrast, the cardiac muscle showed, continuously between E15 and D22, low levels of labeling for both AT1A and AT2 mRNAs, with intensities not visually different at this level of observation.
Microscopic Studies
Aorta
The aorta of the fetus and neonate expressed AT2 receptor mRNA. At E15, this was at a low level in the arterial wall (Fig 2A) but followed at E19 by a high level of expression in the undifferentiated cells of the tunica adventitia and a more moderate level in the outermost layers of the vascular smooth muscles (Fig 2B). The high level of AT2 mRNA expression in the tunica adventitia persisted even after birth (D0) (Fig 2C). Background labeling was seen with the AT2 sense probe (Fig 2D). Ten days after birth, AT2 mRNA expression was nearly absent in the tunica media (Fig 2E) and was decreased in the tunica adventitia, followed by an almost complete disappearance at D22 (Fig 2F) as well as in the adult. In comparison, AT1A receptor mRNA continued to be expressed in these regions at D22 (Fig 2G) as well as in the adult.
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Heart Valves and Coronary Arteries
The heart valves consist of leaflets of connective tissue that extend from the fibrous ring, known as the valve annulus. In the late fetal and neonatal heart (E21 to D3), the valve annulus of each of the four heart valves expressed high levels of AT2 receptor mRNA, whereas the leaflets did not (Fig 3A). At D10, the level of AT2 mRNA expression in the fibrous valve annulus decreased significantly, reaching nearly the background level at D22 (Fig 3B). In the coronary arteries, AT2 receptor mRNA expression first appeared at D0 in isolated cells distributed irregularly around the coronary artery wall. These cells showed strong levels of AT2 receptor mRNA expression between D0 (Fig 3C) and D3, but no expression was observed at D10, D22 (Fig 4C), or in the adult. Occasionally, a few isolated ventricular cells, in proximity to the initial aorta and coronary vessels, showed high expression of AT2 receptor mRNA (Fig 3D). It was not possible to further identify these cells by their histological characteristics.
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Cardiac Muscle
At all stages studied, when observed at the microscopic level, the ventricle exhibited a clear difference in the levels of AT2 and AT1A mRNA expression. At D0, AT2 mRNA expression was not significantly above background levels (Fig 4A), whereas a moderate level of diffuse labeling for AT1A mRNA was detected (Fig 4B). This limited but reproducible difference between AT1A and AT2 mRNA persisted at later stages and in the adult. In the late postnatal (D10 and D22) and adult heart, AT2 mRNA expression was barely detectable (Fig 4C), with the intensity of the hybridization signal being comparable to that produced by the AT2 sense probe (Fig 4D). In the late fetal atria, no hybridization signal was seen for AT2 mRNA, whereas in the early neonatal period (D0 to D3), AT2 receptor mRNA expression was detected but limited to the subendocardial fibroelastic connective tissue (Fig 4E). The entire endocardial lining of the heart cavity and pericardium did not express AT2 receptor mRNA.
Trachea and Lung
AT2 receptor mRNA was abundantly expressed in the trachea (Fig 1) and the entire bronchial tree but was absent in the pulmonary alveolar tissue. Its expression was localized to the submucosal layers and at least some of the smooth muscle cells of the large airways (Fig 4F). All AT2 labeling in these structures disappeared between D10 and D22. AT1A labeling also became undetectable in the lung parenchyma shortly after birth.
Actin Immunostaining
To illustrate a possible correlation between AT2 receptor expression and smooth muscle differentiation, we immunostained sections adjacent to those used for in situ hybridization with an antibody to smooth muscle actin. In the aorta at E19, both AT2 mRNA and actin were detected in the whole thickness of the vessel wall (not shown). However, at D3, only the tunica media stained for actin and not the tunica adventitia (Fig 5A), whereas AT2 mRNA was detected in the tunica adventitia and not in the tunica media (Fig 5B). In coronary arteries, as in the wall of the aorta at D3, AT2 mRNA–labeled cells were located outwardly to the actin-immunostained cells.
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In the walls of the large airways, the layers of smooth muscle cells, ie, cells immunostained for actin (Fig 5C), appeared flanked on both sides by layers of cells that expressed AT2 mRNA (Fig 5D), with little or no overlap of the two labelings.
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Discussion |
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We carried out this study of AT2 receptor mRNA expression by in situ hybridization in the fetal, neonatal, and adult cardiopulmonary system to localize AT2 receptor mRNA at the cellular level and compare its distribution to that of AT1A receptor. Three main observations emerge from this study. First, AT2 mRNA expression is transient in all cardiac and pulmonary structures and reaches a basal level (being undetectable above background) before D22 postpartum and so is apparently not expressed in the adult rat. AT2 receptor mRNA therefore appears to be expressed in a developmentally regulated manner, thus raising the question of its role or roles during the perinatal period. Second, mostly vascular structures and airways, rather than cardiomyocytes or lung parenchyma, express AT2 mRNA. Third, this spatiotemporal pattern of AT2 mRNA expression differs characteristically from that of AT1A mRNA, which is detected both in the walls of large blood vessels and in the cardiac muscle and continues to be expressed at detectable levels throughout neonatal and adult life.
Although the in situ hybridization technique is not rigorously quantitative, we have repeatedly observed a much higher level of AT2 mRNA signal in the large blood vessels than that obtained for AT1A under identical experimental conditions. The transient expression of AT2 mRNA in the cardiopulmonary system during the perinatal and early postnatal periods has not been previously reported. However, a similar temporal pattern of AT2-specific receptor binding sites has been observed in other organs and tissues around birth.21 22 Likewise, we have recently reported the expression and subsequent disappearance of AT2 mRNA in the rat kidney in the first weeks after birth. In contrast, a high level of expression of this mRNA is maintained in the rat adrenal gland, even in the adult.16 23 In the present study, AT2 mRNA expression in the adult rat heart was not detectable above background in any structure, whereas AT1A was easily detected. Using in situ binding autoradiography, Sechi et al10 showed a low level of Ang II receptors corresponding to equal amounts of the AT1 and AT2 receptors. Receptor binding site measurements also indicate an equal amount of AT1 and AT2 receptors on ventricular membranes,3 although another study showed 90% AT2 binding sites in the heart.13 The discrepancy between the results obtained by in situ hybridization and by AT2 binding site measurements may indicate that the protein has a long half-life despite either being transcribed at a low level or the mRNA having a short half-life, thus keeping the AT2 mRNA level below the threshold of detection by in situ hybridization. Alternatively, one cannot exclude the existence of other Ang II receptor subtypes that show similar binding displacement for the nonpeptide AT2 antagonist PD 123319.
Other studies in cell cultures of fetal neonatal and adult rat heart yield various and sometimes discordant results as to the presence and proportion of AT1 and AT2 receptors in fibroblasts and cardiomyocytes.11 14 15 These differences are probably due to the different methodologies and biological materials used. All these results make it difficult to obtain a coherent picture of Ang II receptor expression in the heart during development. In that respect, the present study is the first systematic work on the heart and large blood vessels that, despite its limitations, allows the temporal expression of both AT1 and AT2 receptor mRNAs to be followed at the cellular level under identical experimental conditions.
Although the AT2 receptor is abundantly expressed in fetal tissues, and also in the adult adrenal gland, the exact function and signaling pathways of this receptor remain a subject of debate. Different intracellular signaling mechanisms have been proposed for the AT2 receptor,17 24 25 which mediates several physiological responses to Ang II, such as an increase in the intracellular production of arachidonic acid,25 the growth inhibition of vascular endothelial cells in culture,26 and the induction of collagen synthesis in human cardiac fibroblasts in myocardial fibrosis.27 However, the best documented of Ang II effects mediated by AT2 receptors are on cell proliferation in the aortic wall. In both the adult and late fetus (E16 through E21), AT2 receptors mediate cell proliferation inhibition, either in normal physiological conditions or after balloon injury, thus antagonizing proliferative effects mediated through AT1 receptors.28 29 These examples show that the AT2 receptor may be an active component in the mechanism of action of Ang II and may be functionally significant. In this respect, the decrease of AT2 mRNA expression in the walls of arteries and airways, simultaneously with the differentiation of smooth muscle cells as characterized by smooth muscle actin expression, may represent a clue to the role Ang II plays in development via the AT2 receptor.
However, the fact that mice born without either the AT1A30 or AT231 32 receptor are apparently normal does not support the hypothesis of a role for Ang II in the development of the fetus. The abnormally high blood pressure observed in animals lacking the AT2 receptor, either under normal conditions or in response to Ang II, may result from a modification of the wall thickness, resistance, or elasticity of the large blood vessels and therefore may be a consequence of altered cell differentiation. Such limited histological modifications may have passed unnoticed in the walls of large blood vessels and in the heart of mice lacking the AT2 receptor. The substitutive role of other Ang II receptors cannot be ruled out, such as AT1B for AT1A and an undetermined receptor for AT2.
The high transient and developmentally regulated expression of the AT2 receptor in fetal tissues and organs such as the heart and large blood vessels and airways, as demonstrated in the present study, as well as in the kidney16 and various mesenchymes and muscles,33 strongly suggests a role for the AT2 receptor in organogenesis. It is of note that AT2 mRNA becomes undetectable when an organ has attained its functional maturity. Although studies with nonpeptidic AT1A- and AT2-specific receptor antagonists demonstrate the predominant role of AT1 receptors in mediating most of the known effects of Ang II, the present observations lend support to the hypothesis that the AT2 receptor may play a role in the processes of growth and differentiation.
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Acknowledgments |
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This study was supported by a grant from CIBA-Geigy & Co and by "Naturalia et Biologia." The authors thank Marie-Therese Morin and Francoise Mongiat for technical assistance, Gerard Masquelier for the photographic illustration, Dr Kathleen Curnow for helpful suggestions in the preparation of the manuscript, Nicole Braure for secretarial assistance, and Drs C. Llorens-Cortes and E. Clauser for the gift of the rat AT2 cDNA.
Received November 27, 1995; first decision March 11, 1996; accepted March 11, 1996.
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C. Berry, R. Touyz, A. F. Dominiczak, R. C. Webb, and D. G. Johns Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2337 - H2365. [Abstract] [Full Text] [PDF]
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J. Varagic, D. Susic, and E. D. Frohlich Coronary Hemodynamic and Ventricular Responses to Angiotensin Type 1 Receptor Inhibition in SHR : Interaction With Angiotensin Type 2 Receptors Hypertension, June 1, 2001; 37(6): 1399 - 1403. [Abstract] [Full Text] [PDF]
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 T.-X. Cui, H. Nakagami, M. Iwai, Y. Takeda, T. Shiuchi, L. Daviet, C. Nahmias, and M. Horiuchi Pivotal role of tyrosine phosphatase SHP-1 in AT2 receptor-mediated apoptosis in rat fetal vascular smooth muscle cell Cardiovasc Res, March 1, 2001; 49(4): 863 - 871. [Abstract] [Full Text] [PDF]
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S. L. Malendowicz, P. V. Ennezat, M. Testa, L. Murray, E. H. Sonnenblick, T. Evans, and T. H. LeJemtel Angiotensin II Receptor Subtypes in the Skeletal Muscle Vasculature of Patients With Severe Congestive Heart Failure Circulation, October 31, 2000; 102(18): 2210 - 2213. [Abstract] [Full Text] [PDF]
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T. Matsumoto, R. Ozono, T. Oshima, H. Matsuura, T. Sueda, G. Kajiyama, and M. Kambe Type 2 angiotensin II receptor is downregulated in cardiomyocytes of patients with heart failure Cardiovasc Res, April 1, 2000; 46(1): 73 - 81. [Abstract] [Full Text] [PDF]
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 C. Chassagne, S. Eddahibi, C. Adamy, D. Rideau, F. Marotte, J.-L. Dubois-Randé, S. Adnot, J.-L. Samuel, and E. Teiger Modulation of Angiotensin II Receptor Expression during Development and Regression of Hypoxic Pulmonary Hypertension Am. J. Respir. Cell Mol. Biol., March 1, 2000; 22(3): 323 - 332. [Abstract] [Full Text]
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 M. AKISHITA, M. HORIUCHI, H. YAMADA, L. ZHANG, G. SHIRAKAMI, K. TAMURA, Y. OUCHI, and V. J. DZAU Inflammation influences vascular remodeling through AT2 receptor expression and signaling Physiol Genomics, January 24, 2000; 2(1): 13 - 20. [Abstract] [Full Text] [PDF]
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R. M. Carey, Z.-Q. Wang, and H. M. Siragy Role of the Angiotensin Type 2 Receptor in the Regulation of Blood Pressure and Renal Function Hypertension, January 1, 2000; 35(1): 155 - 163. [Abstract] [Full Text] [PDF]
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K. C Wollert and H. Drexler The renin-angiotensin system and experimental heart failure Cardiovasc Res, September 1, 1999; 43(4): 838 - 849. [Abstract] [Full Text] [PDF]
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S. Lamparter, Y. Sun, and K. T Weber Angiotensin II receptor blockade during gestation attenuates collagen formation in the developing rat heart Cardiovasc Res, July 1, 1999; 43(1): 165 - 172. [Abstract] [Full Text] [PDF]
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H. Yamada, M. Akishita, M. Ito, K. Tamura, L. Daviet, J. Y. A. Lehtonen, V. J. Dzau, and M. Horiuchi AT2 Receptor and Vascular Smooth Muscle Cell Differentiation in Vascular Development Hypertension, June 1, 1999; 33(6): 1414 - 1419. [Abstract] [Full Text] [PDF]
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M. Horiuchi, M. Akishita, and V. J. Dzau Recent Progress in Angiotensin II Type 2 Receptor Research in the Cardiovascular System Hypertension, February 1, 1999; 33(2): 613 - 621. [Abstract] [Full Text] [PDF]
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 H. Matsubara Pathophysiological Role of Angiotensin II Type 2 Receptor in Cardiovascular and Renal Diseases Circ. Res., December 14, 1998; 83(12): 1182 - 1191. [Abstract] [Full Text] [PDF]
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Z.-Q. Wang, A. F. Moore, R. Ozono, H. M. Siragy, and R. M. Carey Immunolocalization of Subtype 2 Angiotensin II (AT2) Receptor Protein in Rat Heart Hypertension, July 1, 1998; 32(1): 78 - 83. [Abstract] [Full Text] [PDF]
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 J. Wharton, K. Morgan, R. A. D. Rutherford, J. D. Catravas, A. Chester, B. F. Whitehead, M. R. D. Leval, M. H. Yacoub, and J. M. Polak Differential Distribution of Angiotensin AT2 Receptors in the Normal and Failing Human Heart J. Pharmacol. Exp. Ther., January 1, 1998; 284(1): 323 - 336. [Abstract] [Full Text]
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R. Ozono, Z.-Q. Wang, A. F. Moore, T. Inagami, H. M. Siragy, and R. M. Carey Expression of the Subtype 2 Angiotensin (AT2) Receptor Protein in Rat Kidney Hypertension, November 1, 1997; 30(5): 1238 - 1246. [Abstract] [Full Text]
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C. Chassagne, C. Adamy, P. Ratajczak, B. Gingras, E. Teiger, E. Planus, P. Oliviero, L. Rappaport, J.-L. Samuel, and S. Meloche Angiotensin II AT2 receptor inhibits smooth muscle cell migration via fibronectin cell production and binding Am J Physiol Cell Physiol, April 1, 2002; 282(4): C654 - C664. [Abstract] [Full Text] [PDF]
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