Role of Renin Angiotensin System in Angiogenesis: It Is Still Elusive
http://www.100md.com
《动脉硬化血栓血管生物学》
From the Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Neovascularization is an integral component of the cardiac remodeling process after myocardial infarction. Numerous and dilated vessels appear in the border zone of infarcted and noninfarcted area after experimental myocardial infarction.1 As a result, coronary vasodilatory capacity resumes to the normal level after several weeks of infarction by an increase in blood flow in the proximal region of the infarcted myocardium. However, it is generally believed that neovascularization after myocardial infarction is limited and insufficient to preserve viable myocardium of the border zone area. A number of clinical and experimental trials of therapeutic angiogenesis, therefore, have been performed to improve cardiac function and survival after myocardial infarction. Several methods including administration of angiogenic growth factors and injection of naked DNA or virus vector that expresses angiogenic factors have been employed. Recent studies have shown that transplantation of bone marrow-derived angioblasts and mesenchymal stem cells are a promising source for tissue regeneration and repair, including neovascularization after myocardial infarction.2,3 Indeed these studies indicated that cardiac function was improved by administration of these progenitor cells, suggesting that neovascularization after myocardial inaction may be beneficial for the infarcted heart. In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, however, the findings of Toko et al4 challenge this view. Toko et al4 show that less neovascularization was induced in AT1a-deficient mice compared with wild type mice after myocardial infarction. It is generally accepted that blockade of the Angiotensin (Ang) II type 1 receptor (AT1) preserves cardiac function after myocardial infarction, and the authors previously demonstrated that left ventricular remodeling was less and the survival rate was improved after myocardial infarction in AT1a-deficient mice.5 These data suggest that cardiac function after myocardial infarction could be preserved without induction of neovascularization. Alternatively, neovascularization does not necessarily contribute to improvement of cardiac function after myocardial infarction. Indeed, a recent report by Norol et al6 indicated that granulocyte-colony stimulating factor (G-CSF) increased myocardial perfusion after myocardial infarction without affecting the myocardial repair process.
See page 664
Numerous clinical and experimental studies have demonstrated that renin angiotensin system (RAS) is critically involved in the development of cardiovascular diseases. It is, however, relatively recent that the role of RAS in angiogenesis has been evaluated, and the results of those studies are inconsistent. Inhibition of angiotensin converting enzyme (ACE) by quinaprilat induced angiogenesis comparable to vascular endothelial growth factor (VEGF) in a hind limb ischemic model.7 The effect of captopril was weaker than that of quinaprilat, and it was suggested that ACE inhibitor with high tissue affinity may be useful for therapeutic angiogenesis. Silvestre et al8 reported that the proangiogenic effect of ACE inhibitors was mediated through bradykinin B2 receptor pathway, because perindopril enhanced reparative angiogenesis induced by hind-limb ischemia in wild type mice but not in bradykinin B2 receptor knockout mice. In contrast, it was reported that captopril inhibited angiogenesis in tumors and cornea.9 The antiangiogenic effect was not observed with lisinopril or enalapril, suggesting that the antiangiogenic effect might be proper to captopril rather than a class effect of ACE inhibitors. In another report, perindopril inhibited angiogenesis and metastasis of hepatocellular carcinoma with concomitant reduction of VEGF expression.10 In addition, lisinopril reduced progression of retinopathy in normotensive patients with type 1 diabetes mellitus in the EURODIAB Controlled Trial of Lisinopril in Insulin Dependent Diabetes study.11 It is not clear at this point whether these contradicting results stem from the different models examined or differential property of ACE inhibitors used.
One of the major angiogenic factors is VEGF. Many reports have indicated that VEGF activates new vessel formation in many tissue types. Tissue hypoxia is a strong stimulus for VEGF expression. Hypoxia induces expression of the transcription factor designated hypoxia-inducible factor-1 (HIF-1) by inhibiting degradation of the protein, which in turn activates VEGF expression through binding to hypoxic response element of VEGF gene promoter.12 It has been reported that angiotensin II also induces expression of VEGF in vascular smooth muscle cells under nonhypoxic conditions.13 This is caused by induction of HIF-1 by angiotensin II through AT1. Angiotensin II increases HIF-1 gene expression through transcriptional and posttranscriptional mechanisms.14 Protein kinase C is involved in HIF-1 gene activation, whereas phosphatidylinositol 3-kinase pathway is important for HIF-1 mRNA stabilization. AngII-induced VEGF expression in endothelial cells is also mediated via AT1.15 Therefore, experiments at the cellular level strongly support the idea that activation of AT1 mediates angiogenesis.
In mice lacking AT1a, angiogenesis induced by hind-limb ischemia was impaired compared with wild type mice.16 Although AT1a-deficient mice show substantial decrease in blood pressure compared with wild type mice, the effect was blood pressure-independent because reduction of blood pressure comparable to AT1-deficient mice did not affect angiogenesis in wild type mice. Candesartan, one of the AT1 antagonists clinically used, at doses that did not affect blood pressure level also inhibited angiogenesis in wild type mice after hind-limb ischemia. These two different approaches to inhibit AT1 signal confirmed that activation of AT1 was proangiogenic. It was also reported that tumor-associated angiogenesis was impaired in the AT1a-deficient mice.17 AT1 receptor expressed on tumor-associated macrophages mediates VEGF expression and angiogenesis. Another report showed that Ang II infusion increased capillary density in a hind-limb ischemia model with increased expression levels of VEGF and endothelial nitric oxide synthase (eNOS).18 Toko et al4 show that neovascularization after myocardial infarction is less prominent in AT1-deficient mice with reduced infiltration of granulocytes and macrophage and expression of chemokines and interleukins compared with control mice. NOS activity was also decreased in AT1a-deficient mice. The results by Toko et al4 are consistent with those indicated in the hind-limb ischemia model noted above and confirm the proangiogenic effect of AT1a and the role of NOS as a possible downstream effector molecule of AT1a in neovascularization after myocardial infarction. However, it has not been determined which cell types are responsible for the production of these cytokines and chemokines, therefore it is not clear whether reduction of cell infiltration is a cause or result of increased cytokine or chemokine production. Another issue that is not solved is the role of AT1b in the AT1a-deficient mice. Although the relative contribution of AT1b to blood pressure is minor compared with that of AT1a, AT1b mediates pressor response to AngII in the absence of AT1a.19 Future studies examining AT1a/b double-knockout mice will be needed to address the role of AT1b.
In contrast to AT1, it was reported that angiotensin II type 2 receptor (AT2) inhibited angiogenesis. We previously showed that vessel density and perfusion in ischemic hind limb was higher in AT2 knockout mice compared with control mice.20 This was accompanied by an increase in Bcl-2, an antiapoptotic protein, and a decreased in apoptotic cell death indicated by TUNEL method. A recent report by Benndorf et al21 showed that Ang II inhibited VEGF-induced migration and tube formation of endothelial cells through AT2. Activation of AT2 inhibited VEGF-induced phosphorylation of Akt and eNOS. These effects may account for the antiangiogenic properties of AT2. The role of AT2 has not been examined in the report by Toko et al.4
Although AT1 seems to exert a proangiogenic effect and AT2 seems to show an antiangiogenic effect, many conflicting data are also reported. Walther et al22 showed that AT1 inhibited angiogenesis, whereas AT2 stimulated angiogenesis by using an alginate implant angiogenesis model in mice. Furthermore, de Boer et al23 reported that microvessel density after myocardial infarction was decreased in transgenic rats overexpressing AT1 in the heart, and decreased microvessel density was reversed by losartan. To date, different strategies and models have been used to examine the role of RAS (role of receptor subtypes, effect of ACE inhibitors or receptor antagonists) in angiogenesis, and the results are contradictory. The difference may partly result from the fact that the effect on angiogenesis is strongly dependent on the model. Opposing findings, for example, have been reported in AT2-deficient mice in the hind-limb ischemia model18 and the alginate implant model.22 Therefore, the data on angiogenesis must be carefully reviewed based on the experimental model, animal, and pharmacological treatments.
In conclusion, the study by Toko et al4 clearly reveals that AT1 is proangiogenic after myocardial infarction. However, the role of RAS in angiogenesis is still elusive because of many conflicting reports. The results by Toko et al4 also raise an important issue on the role of neovascularization in the preservation of cardiac function after myocardial infarction and warrants further investigations in this field.
Acknowledgments
This study was supported in part by grants from Takeda Medical Research Foundation and Mitsubishi Pharma Research Foundation, and a Grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. (14570673)
References
Nelissen-Vrancken HJ, Debets JJ, Snoeckx LH, Daemen MJ, Smits JF. Time-related normalization of maximal coronary flow in isolated perfused hearts of rats with myocardial infarction. Circulation. 1996; 93: 349–355.
Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, Itescu S. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med. 2001; 7: 430–436.
Tang YL, Zhao Q, Zhang YC, Cheng L, Liu M, Shi J, Yang YZ, Pan C, Ge J, Phillips MI. Autologous mesenchymal stem cell transplantation induce VEGF and neovascularization in ischemic myocardium. Regul Pept. 2004; 117: 3–10.
Toko H, Zou Y, Minamino T, Sakamoto M, Sano M, Harada M, Nagai T, Sugaya T, Terasaki F, Kitaura Y, Komuro I. Angiotensin II type 1a receptor is involved in cell infiltration, cytokine production, and neovascularization in infarcted myocardium. Arterioscler Thromb Vasc Biol. 2004; 24: 664–670.
Harada K, Sugaya T, Murakami K, Yazaki Y, Komuro I. Angiotensin II type 1A receptor knockout mice display less left ventricular remodeling and improved survival after myocardial infarction. Circulation. 1999; 100: 2093–2099.
Norol F, Merlet P, Isnard R, Sebillon P, Bonnet N, Cailliot C, Carrion C, Ribeiro M, Charlotte F, Pradeau P, Mayol JF, Peinnequin A, Drouet M, Safsafi K, Vernant JP, Herodin F. Influence of mobilized stem cells on myocardial infarct repair in a nonhuman primate model. Blood. 2003; 102: 4361–4368.
Fabre JE, Rivard A, Magner M, Silver M, Isner JM. Tissue inhibition of angiotensin-converting enzyme activity stimulates angiogenesis in vivo. Circulation. 1999; 99: 3043–3049.
Silvestre JS, Bergaya S, Tamarat R, Duriez M, Boulanger CM, Levy BI. Proangiogenic effect of angiotensin-converting enzyme inhibition is mediated by the bradykinin B(2) receptor pathway. Circ Res. 2001; 89: 678–683.
Volpert OV, Ward WF, Lingen MW, Chesler L, Solt DB, Johnson MD, Molteni A, Polverini PJ, Bouck NP. Captopril inhibits angiogenesis and slows the growth of experimental tumors in rats. J Clin Invest. 1996; 98: 671–679.
Yoshiji H, Kuriyama S, Kawata M, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T, Tsujinoue H, Fukui H. The angiotensin-I-converting enzyme inhibitor perindopril suppresses tumor growth and angiogenesis: possible role of the vascular endothelial growth factor. Clin Cancer Res. 2001; 7: 1073–1078.
Chaturvedi N, Sjolie AK, Stephenson JM, Abrahamian H, Keipes M, Castellarin A, Rogulja-Pepeonik Z, Fuller JH. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet. 1998; 351: 28–31.
Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995; 92: 5510–5514.
Williams B, Baker AQ, Gallacher B, Lodwick D. Angiotensin II increases vascular permeability factor gene expression by human vascular smooth muscle cells. Hypertension. 1995; 25: 913–917.
Page EL, Robitaille GA, Pouyssegur J, Richard DE. Induction of hypoxia-inducible factor-1 by transcriptional and translational mechanisms. J Biol Chem. 2002; 277: 48403–48409.
Chua CC, Hamdy RC, Chua BH. Upregulation of vascular endothelial growth factor by angiotensin II in rat heart endothelial cells. Biochim Biophys Acta. 1998; 1401: 187–194.
Sasaki K, Murohara T, Ikeda H, Sugaya T, Shimada T, Shintani S, Imaizumi T. Evidence for the importance of angiotensin II type 1 receptor in ischemia-induced angiogenesis. J Clin Invest. 2002; 109: 603–611.
Egami K, Murohara T, Shimada T, Sasaki K, Shintani S, Sugaya T, Ishii M, Akagi T, Ikeda H, Matsuishi T, Imaizumi T. Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth. J Clin Invest. 2003; 112: 67–75.
Tamarat R, Silvestre JS, Kubis N, Benessiano J, Duriez M, deGasparo M, Henrion D, Levy BI. Endothelial nitric oxide synthase lies downstream from angiotensin II-induced angiogenesis in ischemic hindlimb. Hypertension. 2002; 39: 830–835.
Oliverio MI, Best CF, Kim HS, Arendshorst WJ, Smithies O, Coffman TM. Angiotensin II responses in AT1A receptor-deficient mice: a role for AT1B receptors in blood pressure regulation. Am J Physiol. 1997; 272: F515–F520.
Silvestre JS, Tamarat R, Senbonmatsu T, Ichiki T, Ebrahimian T, Iglarz M, Besnard S, Duriez M, Inagami T, Levy BI. Antiangiogenic effect of angiotensin II type 2 receptor in ischemia-induced angiogenesis in mice hindlimb. Circ Res. 2002; 90: 1072–1079.
Benndorf R, Boger RH, Ergun S, Steenpass A, Wieland T. Angiotensin II type 2 receptor inhibits vascular endothelial growth factor-induced migration and in vitro tube formation of human endothelial cells. Circ Res. 2003; 93: 438–447.
Walther T, Menrad A, Orzechowski HD, Siemeister G, Paul M, Schirner M. Differential regulation of in vivo angiogenesis by angiotensin II receptors. FASEB J. 2003; 17: 2061–2067.
de Boer RA, Pinto YM, Suurmeijer AJ, Pokharel S, Scholtens E, Humler M, Saavedra JM, Boomsma F, van Gilst WH, van Veldhuisen DJ. Increased expression of cardiac angiotensin II type 1 (AT(1)) receptors decreases myocardial microvessel density after experimental myocardial infarction. Cardiovasc Res. 2003; 57: 434–442.(Toshihiro Ichiki)
Neovascularization is an integral component of the cardiac remodeling process after myocardial infarction. Numerous and dilated vessels appear in the border zone of infarcted and noninfarcted area after experimental myocardial infarction.1 As a result, coronary vasodilatory capacity resumes to the normal level after several weeks of infarction by an increase in blood flow in the proximal region of the infarcted myocardium. However, it is generally believed that neovascularization after myocardial infarction is limited and insufficient to preserve viable myocardium of the border zone area. A number of clinical and experimental trials of therapeutic angiogenesis, therefore, have been performed to improve cardiac function and survival after myocardial infarction. Several methods including administration of angiogenic growth factors and injection of naked DNA or virus vector that expresses angiogenic factors have been employed. Recent studies have shown that transplantation of bone marrow-derived angioblasts and mesenchymal stem cells are a promising source for tissue regeneration and repair, including neovascularization after myocardial infarction.2,3 Indeed these studies indicated that cardiac function was improved by administration of these progenitor cells, suggesting that neovascularization after myocardial inaction may be beneficial for the infarcted heart. In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, however, the findings of Toko et al4 challenge this view. Toko et al4 show that less neovascularization was induced in AT1a-deficient mice compared with wild type mice after myocardial infarction. It is generally accepted that blockade of the Angiotensin (Ang) II type 1 receptor (AT1) preserves cardiac function after myocardial infarction, and the authors previously demonstrated that left ventricular remodeling was less and the survival rate was improved after myocardial infarction in AT1a-deficient mice.5 These data suggest that cardiac function after myocardial infarction could be preserved without induction of neovascularization. Alternatively, neovascularization does not necessarily contribute to improvement of cardiac function after myocardial infarction. Indeed, a recent report by Norol et al6 indicated that granulocyte-colony stimulating factor (G-CSF) increased myocardial perfusion after myocardial infarction without affecting the myocardial repair process.
See page 664
Numerous clinical and experimental studies have demonstrated that renin angiotensin system (RAS) is critically involved in the development of cardiovascular diseases. It is, however, relatively recent that the role of RAS in angiogenesis has been evaluated, and the results of those studies are inconsistent. Inhibition of angiotensin converting enzyme (ACE) by quinaprilat induced angiogenesis comparable to vascular endothelial growth factor (VEGF) in a hind limb ischemic model.7 The effect of captopril was weaker than that of quinaprilat, and it was suggested that ACE inhibitor with high tissue affinity may be useful for therapeutic angiogenesis. Silvestre et al8 reported that the proangiogenic effect of ACE inhibitors was mediated through bradykinin B2 receptor pathway, because perindopril enhanced reparative angiogenesis induced by hind-limb ischemia in wild type mice but not in bradykinin B2 receptor knockout mice. In contrast, it was reported that captopril inhibited angiogenesis in tumors and cornea.9 The antiangiogenic effect was not observed with lisinopril or enalapril, suggesting that the antiangiogenic effect might be proper to captopril rather than a class effect of ACE inhibitors. In another report, perindopril inhibited angiogenesis and metastasis of hepatocellular carcinoma with concomitant reduction of VEGF expression.10 In addition, lisinopril reduced progression of retinopathy in normotensive patients with type 1 diabetes mellitus in the EURODIAB Controlled Trial of Lisinopril in Insulin Dependent Diabetes study.11 It is not clear at this point whether these contradicting results stem from the different models examined or differential property of ACE inhibitors used.
One of the major angiogenic factors is VEGF. Many reports have indicated that VEGF activates new vessel formation in many tissue types. Tissue hypoxia is a strong stimulus for VEGF expression. Hypoxia induces expression of the transcription factor designated hypoxia-inducible factor-1 (HIF-1) by inhibiting degradation of the protein, which in turn activates VEGF expression through binding to hypoxic response element of VEGF gene promoter.12 It has been reported that angiotensin II also induces expression of VEGF in vascular smooth muscle cells under nonhypoxic conditions.13 This is caused by induction of HIF-1 by angiotensin II through AT1. Angiotensin II increases HIF-1 gene expression through transcriptional and posttranscriptional mechanisms.14 Protein kinase C is involved in HIF-1 gene activation, whereas phosphatidylinositol 3-kinase pathway is important for HIF-1 mRNA stabilization. AngII-induced VEGF expression in endothelial cells is also mediated via AT1.15 Therefore, experiments at the cellular level strongly support the idea that activation of AT1 mediates angiogenesis.
In mice lacking AT1a, angiogenesis induced by hind-limb ischemia was impaired compared with wild type mice.16 Although AT1a-deficient mice show substantial decrease in blood pressure compared with wild type mice, the effect was blood pressure-independent because reduction of blood pressure comparable to AT1-deficient mice did not affect angiogenesis in wild type mice. Candesartan, one of the AT1 antagonists clinically used, at doses that did not affect blood pressure level also inhibited angiogenesis in wild type mice after hind-limb ischemia. These two different approaches to inhibit AT1 signal confirmed that activation of AT1 was proangiogenic. It was also reported that tumor-associated angiogenesis was impaired in the AT1a-deficient mice.17 AT1 receptor expressed on tumor-associated macrophages mediates VEGF expression and angiogenesis. Another report showed that Ang II infusion increased capillary density in a hind-limb ischemia model with increased expression levels of VEGF and endothelial nitric oxide synthase (eNOS).18 Toko et al4 show that neovascularization after myocardial infarction is less prominent in AT1-deficient mice with reduced infiltration of granulocytes and macrophage and expression of chemokines and interleukins compared with control mice. NOS activity was also decreased in AT1a-deficient mice. The results by Toko et al4 are consistent with those indicated in the hind-limb ischemia model noted above and confirm the proangiogenic effect of AT1a and the role of NOS as a possible downstream effector molecule of AT1a in neovascularization after myocardial infarction. However, it has not been determined which cell types are responsible for the production of these cytokines and chemokines, therefore it is not clear whether reduction of cell infiltration is a cause or result of increased cytokine or chemokine production. Another issue that is not solved is the role of AT1b in the AT1a-deficient mice. Although the relative contribution of AT1b to blood pressure is minor compared with that of AT1a, AT1b mediates pressor response to AngII in the absence of AT1a.19 Future studies examining AT1a/b double-knockout mice will be needed to address the role of AT1b.
In contrast to AT1, it was reported that angiotensin II type 2 receptor (AT2) inhibited angiogenesis. We previously showed that vessel density and perfusion in ischemic hind limb was higher in AT2 knockout mice compared with control mice.20 This was accompanied by an increase in Bcl-2, an antiapoptotic protein, and a decreased in apoptotic cell death indicated by TUNEL method. A recent report by Benndorf et al21 showed that Ang II inhibited VEGF-induced migration and tube formation of endothelial cells through AT2. Activation of AT2 inhibited VEGF-induced phosphorylation of Akt and eNOS. These effects may account for the antiangiogenic properties of AT2. The role of AT2 has not been examined in the report by Toko et al.4
Although AT1 seems to exert a proangiogenic effect and AT2 seems to show an antiangiogenic effect, many conflicting data are also reported. Walther et al22 showed that AT1 inhibited angiogenesis, whereas AT2 stimulated angiogenesis by using an alginate implant angiogenesis model in mice. Furthermore, de Boer et al23 reported that microvessel density after myocardial infarction was decreased in transgenic rats overexpressing AT1 in the heart, and decreased microvessel density was reversed by losartan. To date, different strategies and models have been used to examine the role of RAS (role of receptor subtypes, effect of ACE inhibitors or receptor antagonists) in angiogenesis, and the results are contradictory. The difference may partly result from the fact that the effect on angiogenesis is strongly dependent on the model. Opposing findings, for example, have been reported in AT2-deficient mice in the hind-limb ischemia model18 and the alginate implant model.22 Therefore, the data on angiogenesis must be carefully reviewed based on the experimental model, animal, and pharmacological treatments.
In conclusion, the study by Toko et al4 clearly reveals that AT1 is proangiogenic after myocardial infarction. However, the role of RAS in angiogenesis is still elusive because of many conflicting reports. The results by Toko et al4 also raise an important issue on the role of neovascularization in the preservation of cardiac function after myocardial infarction and warrants further investigations in this field.
Acknowledgments
This study was supported in part by grants from Takeda Medical Research Foundation and Mitsubishi Pharma Research Foundation, and a Grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. (14570673)
References
Nelissen-Vrancken HJ, Debets JJ, Snoeckx LH, Daemen MJ, Smits JF. Time-related normalization of maximal coronary flow in isolated perfused hearts of rats with myocardial infarction. Circulation. 1996; 93: 349–355.
Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, Itescu S. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med. 2001; 7: 430–436.
Tang YL, Zhao Q, Zhang YC, Cheng L, Liu M, Shi J, Yang YZ, Pan C, Ge J, Phillips MI. Autologous mesenchymal stem cell transplantation induce VEGF and neovascularization in ischemic myocardium. Regul Pept. 2004; 117: 3–10.
Toko H, Zou Y, Minamino T, Sakamoto M, Sano M, Harada M, Nagai T, Sugaya T, Terasaki F, Kitaura Y, Komuro I. Angiotensin II type 1a receptor is involved in cell infiltration, cytokine production, and neovascularization in infarcted myocardium. Arterioscler Thromb Vasc Biol. 2004; 24: 664–670.
Harada K, Sugaya T, Murakami K, Yazaki Y, Komuro I. Angiotensin II type 1A receptor knockout mice display less left ventricular remodeling and improved survival after myocardial infarction. Circulation. 1999; 100: 2093–2099.
Norol F, Merlet P, Isnard R, Sebillon P, Bonnet N, Cailliot C, Carrion C, Ribeiro M, Charlotte F, Pradeau P, Mayol JF, Peinnequin A, Drouet M, Safsafi K, Vernant JP, Herodin F. Influence of mobilized stem cells on myocardial infarct repair in a nonhuman primate model. Blood. 2003; 102: 4361–4368.
Fabre JE, Rivard A, Magner M, Silver M, Isner JM. Tissue inhibition of angiotensin-converting enzyme activity stimulates angiogenesis in vivo. Circulation. 1999; 99: 3043–3049.
Silvestre JS, Bergaya S, Tamarat R, Duriez M, Boulanger CM, Levy BI. Proangiogenic effect of angiotensin-converting enzyme inhibition is mediated by the bradykinin B(2) receptor pathway. Circ Res. 2001; 89: 678–683.
Volpert OV, Ward WF, Lingen MW, Chesler L, Solt DB, Johnson MD, Molteni A, Polverini PJ, Bouck NP. Captopril inhibits angiogenesis and slows the growth of experimental tumors in rats. J Clin Invest. 1996; 98: 671–679.
Yoshiji H, Kuriyama S, Kawata M, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T, Tsujinoue H, Fukui H. The angiotensin-I-converting enzyme inhibitor perindopril suppresses tumor growth and angiogenesis: possible role of the vascular endothelial growth factor. Clin Cancer Res. 2001; 7: 1073–1078.
Chaturvedi N, Sjolie AK, Stephenson JM, Abrahamian H, Keipes M, Castellarin A, Rogulja-Pepeonik Z, Fuller JH. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet. 1998; 351: 28–31.
Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995; 92: 5510–5514.
Williams B, Baker AQ, Gallacher B, Lodwick D. Angiotensin II increases vascular permeability factor gene expression by human vascular smooth muscle cells. Hypertension. 1995; 25: 913–917.
Page EL, Robitaille GA, Pouyssegur J, Richard DE. Induction of hypoxia-inducible factor-1 by transcriptional and translational mechanisms. J Biol Chem. 2002; 277: 48403–48409.
Chua CC, Hamdy RC, Chua BH. Upregulation of vascular endothelial growth factor by angiotensin II in rat heart endothelial cells. Biochim Biophys Acta. 1998; 1401: 187–194.
Sasaki K, Murohara T, Ikeda H, Sugaya T, Shimada T, Shintani S, Imaizumi T. Evidence for the importance of angiotensin II type 1 receptor in ischemia-induced angiogenesis. J Clin Invest. 2002; 109: 603–611.
Egami K, Murohara T, Shimada T, Sasaki K, Shintani S, Sugaya T, Ishii M, Akagi T, Ikeda H, Matsuishi T, Imaizumi T. Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth. J Clin Invest. 2003; 112: 67–75.
Tamarat R, Silvestre JS, Kubis N, Benessiano J, Duriez M, deGasparo M, Henrion D, Levy BI. Endothelial nitric oxide synthase lies downstream from angiotensin II-induced angiogenesis in ischemic hindlimb. Hypertension. 2002; 39: 830–835.
Oliverio MI, Best CF, Kim HS, Arendshorst WJ, Smithies O, Coffman TM. Angiotensin II responses in AT1A receptor-deficient mice: a role for AT1B receptors in blood pressure regulation. Am J Physiol. 1997; 272: F515–F520.
Silvestre JS, Tamarat R, Senbonmatsu T, Ichiki T, Ebrahimian T, Iglarz M, Besnard S, Duriez M, Inagami T, Levy BI. Antiangiogenic effect of angiotensin II type 2 receptor in ischemia-induced angiogenesis in mice hindlimb. Circ Res. 2002; 90: 1072–1079.
Benndorf R, Boger RH, Ergun S, Steenpass A, Wieland T. Angiotensin II type 2 receptor inhibits vascular endothelial growth factor-induced migration and in vitro tube formation of human endothelial cells. Circ Res. 2003; 93: 438–447.
Walther T, Menrad A, Orzechowski HD, Siemeister G, Paul M, Schirner M. Differential regulation of in vivo angiogenesis by angiotensin II receptors. FASEB J. 2003; 17: 2061–2067.
de Boer RA, Pinto YM, Suurmeijer AJ, Pokharel S, Scholtens E, Humler M, Saavedra JM, Boomsma F, van Gilst WH, van Veldhuisen DJ. Increased expression of cardiac angiotensin II type 1 (AT(1)) receptors decreases myocardial microvessel density after experimental myocardial infarction. Cardiovasc Res. 2003; 57: 434–442.(Toshihiro Ichiki)