© 2001 American Heart Association, Inc.
Molecular Medicine |
Angiotensin AT1 and AT2 Receptors Differentially Regulate Angiopoietin-2 and Vascular Endothelial Growth Factor Expression and Angiogenesis by Modulating Heparin Binding–Epidermal Growth Factor (EGF)–Mediated EGF Receptor Transactivation
From the Departments of Medicine II (S.F., H. Matsubara, K.M., Y.M., Y.T., H. Masaki, Y.U., Y.K., A.N., O.I., E.T., T.I.) and Ophthalmology (N.J., N.O.), Kansai Medical University, Osaka; Pharmacological Laboratory (Y.N.), Taiho Pharmaceutical Co. Ltd., Tokushima; and Department of Biochemistry (S.H.), School of Allied Health Science, Osaka University Faculty of Medicine, Osaka, Japan.
Correspondence to Hiroaki Matsubara, M.D., Department of Medicine II, Kansai Medical University, Fumizonocho 10-15, Moriguchi, Osaka 570-8507, Japan. E-mail matsubah{at}takii.kmu.ac.jp
Abstract—Angiotensin II (Ang II)–mediated signals are transmitted via heparin binding epidermal growth factor (EGF)–like growth factor (HB-EGF) release followed by transactivation of EGF receptor (EGFR). Although Ang II and HB-EGF induce angiogenesis, their link to the angiopoietin (Ang)–Tie2 system remains undefined. We tested the effects of Ang II on Ang1, Ang2, or Tie2 expression in cardiac microvascular endothelial cells expressing the Ang II receptors AT1 and AT2. Ang II significantly induced Ang2 mRNA accumulations without affecting Ang1 or Tie2 expression, which was inhibited by protein kinase C inhibitors and by intracellular Ca2+ chelating agents. Ang II transactivated EGFR via AT1, and inhibition of EGFR abolished the induction of Ang2. Ang II caused processing of pro–HB-EGF in a metalloproteinase-dependent manner to stimulate maturation and release of HB-EGF. Neutralizing anti–HB-EGF antibody blocked EGFR phosphorylation by Ang II. Ang II also upregulated vascular endothelial growth factor (VEGF) expression in an HB-EGF/EGFR–dependent manner. AT2 inhibited AT1-mediated Ang2 expression and phosphorylation of EGFR. In an in vivo corneal assay, AT1 induced angiogenesis in an HB-EGF–dependent manner and enhanced the angiogenic activity of VEGF. Although neither Ang2 nor Ang1 alone induced angiogenesis, soluble Tie2-Fc that binds to angiopoietins attenuated AT1-mediated angiogenesis. These findings suggested that (1) Ang II induces Ang2 and VEGF expression without affecting Ang1 or Tie2 and (2) AT1 stimulates processing of pro–HB-EGF by metalloproteinases, and the released HB-EGF transactivates EGFR to induce angiogenesis via the combined effect of Ang2 and VEGF, whereas AT2 attenuates them by blocking EGFR phosphorylation. Thus, Ang II is involved in the VEGF-Ang-Tie2 system via HB-EGF–mediated EGFR transactivation, and this link should be considerable in pathological conditions in which collateral blood flow is required.
Key Words: angiotensin II • angiopoietin • angiogenesis • vascular endothelial growth factor • endothelial cell
This article has been cited by other articles:
 |
|
 |
|
  M. N. Schilte, J. W.A.M Celie, P. M. t. Wee, R. H.J. Beelen, and J. van den Born FACTORS CONTRIBUTING TO PERITONEAL TISSUE REMODELING IN PERITONEAL DIALYSIS Perit. Dial. Int., November 1, 2009; 29(6): 605 - 617. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Clapp, S. Thebault, M. C. Jeziorski, and G. Martinez De La Escalera Peptide Hormone Regulation of Angiogenesis Physiol Rev, October 1, 2009; 89(4): 1177 - 1215. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Belmadani, K. Matrougui, C. Kolz, Y. F. Pung, D. Palen, D. J. Prockop, and W. M. Chilian Amplification of Coronary Arteriogenic Capacity of Multipotent Stromal Cells by Epidermal Growth Factor Arterioscler Thromb Vasc Biol, June 1, 2009; 29(6): 802 - 808. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Walter, N. Etienne-Selloum, D. Brasse, R. Schleiffer, V. Bekaert, P. M. Vanhoutte, A. Beretz, and V. B. Schini-Kerth Red Wine Polyphenols Prevent Acceleration of Neovascularization by Angiotensin II in the Ischemic Rat Hindlimb J. Pharmacol. Exp. Ther., May 1, 2009; 329(2): 699 - 707. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. I. Ager, J. Neo, and C. Christophi The renin-angiotensin system and malignancy Carcinogenesis, September 1, 2008; 29(9): 1675 - 1684. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Su, P. A. Lucchesi, R. A. Gonzalez-Villalobos, D. I. Palen, B. M. Rezk, Y. Suzuki, H. A. Boulares, and K. Matrougui Role of Advanced Glycation End Products With Oxidative Stress in Resistance Artery Dysfunction in Type 2 Diabetic Mice Arterioscler Thromb Vasc Biol, August 1, 2008; 28(8): 1432 - 1438. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Urayama, C. Guilini, N. Messaddeq, K. Hu, M. Steenman, H. Kurose, G. Ert, and C. G. Nebigil The prokineticin receptor-1 (GPR73) promotes cardiomyocyte survival and angiogenesis FASEB J, September 1, 2007; 21(11): 2980 - 2993. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hladunewich, S. A. Karumanchi, and R. Lafayette Pathophysiology of the Clinical Manifestations of Preeclampsia Clin. J. Am. Soc. Nephrol., May 1, 2007; 2(3): 543 - 549. [Full Text] [PDF]
|
|
|
|
 |
|
 F.-C. Ye, D. J. Blackbourn, M. Mengel, J.-P. Xie, L.-W. Qian, W. Greene, I-T. Yeh, D. Graham, and S.-J. Gao Kaposi's Sarcoma-Associated Herpesvirus Promotes Angiogenesis by Inducing Angiopoietin-2 Expression via AP-1 and Ets1 J. Virol., April 15, 2007; 81(8): 3980 - 3991. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Niu and W. B. Carter Human Epidermal Growth Factor Receptor 2 Regulates Angiopoietin-2 Expression in Breast Cancer via AKT and Mitogen-Activated Protein Kinase Pathways Cancer Res., February 15, 2007; 67(4): 1487 - 1493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ohtsu, P. J. Dempsey, G. D. Frank, E. Brailoiu, S. Higuchi, H. Suzuki, H. Nakashima, K. Eguchi, and S. Eguchi ADAM17 Mediates Epidermal Growth Factor Receptor Transactivation and Vascular Smooth Muscle Cell Hypertrophy Induced by Angiotensin II Arterioscler Thromb Vasc Biol, September 1, 2006; 26(9): e133 - e137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ushio-Fukai Redox signaling in angiogenesis: Role of NADPH oxidase Cardiovasc Res, July 15, 2006; 71(2): 226 - 235. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Ohtsu, P. J. Dempsey, and S. Eguchi ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors Am J Physiol Cell Physiol, July 1, 2006; 291(1): C1 - C10. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. de Resende, S. L. Amaral, D. H. Munzenmaier, and A. S. Greene Role of endothelial cell apoptosis in regulation of skeletal muscle angiogenesis during high and low salt intake Physiol Genomics, April 13, 2006; 25(2): 325 - 335. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Feliers, Y. Gorin, G. Ghosh-Choudhury, H. E. Abboud, and B. S. Kasinath Angiotensin II stimulation of VEGF mRNA translation requires production of reactive oxygen species Am J Physiol Renal Physiol, April 1, 2006; 290(4): F927 - F936. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. H. Munzenmaier and A. S. Greene Chronic angiotensin II AT1 receptor blockade increases cerebral cortical microvessel density Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H512 - H516. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Rondelet, F. Kerbaul, R. Van Beneden, I. Hubloue, S. Huez, P. Fesler, M. Remmelink, S. Brimioulle, I. Salmon, and R. Naeije Prevention of pulmonary vascular remodeling and of decreased BMPR-2 expression by losartan therapy in shunt-induced pulmonary hypertension Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2319 - H2324. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Uemura, H. Ishiguro, Y. Nagashima, T. Sasaki, N. Nakaigawa, H. Hasumi, S. Kato, and Y. Kubota Antiproliferative activity of angiotensin II receptor blocker through cross-talk between stromal and epithelial prostate cancer cells Mol. Cancer Ther., November 1, 2005; 4(11): 1699 - 1709. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. D. Nelin, L. G. Chicoine, K. M. Reber, B. K. English, T. L. Young, and Y. Liu Cytokine-Induced Endothelial Arginase Expression Is Dependent on Epidermal Growth Factor Receptor Am. J. Respir. Cell Mol. Biol., October 1, 2005; 33(4): 394 - 401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kanehira, T. Tani, T. Takagi, Y. Nakano, E. F. Howard, and M. Tamura Angiotensin II Type 2 Receptor Gene Deficiency Attenuates Susceptibility to Tobacco-Specific Nitrosamine-Induced Lung Tumorigenesis: Involvement of Transforming Growth Factor-{beta}-Dependent Cell Growth Attenuation Cancer Res., September 1, 2005; 65(17): 7660 - 7665. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Chalothorn, S. M. Moore, H. Zhang, S. W. Sunnarborg, D. C. Lee, and J. E. Faber Heparin-Binding Epidermal Growth Factor-Like Growth Factor, Collateral Vessel Development, and Angiogenesis in Skeletal Muscle Ischemia Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1884 - 1890. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Chalothorn, H. Zhang, J. A. Clayton, S. A. Thomas, and J. E. Faber Catecholamines augment collateral vessel growth and angiogenesis in hindlimb ischemia Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H947 - H959. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Mifune, H. Ohtsu, H. Suzuki, H. Nakashima, E. Brailoiu, N. J. Dun, G. D. Frank, T. Inagami, S. Higashiyama, W. G. Thomas, et al. G Protein Coupling and Second Messenger Generation Are Indispensable for Metalloprotease-dependent, Heparin-binding Epidermal Growth Factor Shedding through Angiotensin II Type-1 Receptor J. Biol. Chem., July 15, 2005; 280(28): 26592 - 26599. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Takeda, Y. Katagata, Y. Hozumi, and S. Kondo Effects of Angiotensin II Receptor Signaling during Skin Wound Healing Am. J. Pathol., November 1, 2004; 165(5): 1653 - 1662. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Rondelet, F. Kerbaul, R. Van Beneden, S. Motte, P. Fesler, I. Hubloue, M. Remmelink, S. Brimioulle, I. Salmon, J.-M. Ketelslegers, et al. Signaling Molecules in Overcirculation-Induced Pulmonary Hypertension in Piglets: Effects of Sildenafil Therapy Circulation, October 12, 2004; 110(15): 2220 - 2225. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Zhang, M. Lassila, M. E. Cooper, and Z. Cao Retinal Expression of Vascular Endothelial Growth Factor Is Mediated by Angiotensin Type 1 and Type 2 Receptors Hypertension, February 1, 2004; 43(2): 276 - 281. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Rizkalla, J. M. Forbes, M. E. Cooper, and Z. Cao Increased Renal Vascular Endothelial Growth Factor and Angiopoietins by Angiotensin II Infusion Is Mediated by Both AT1 and AT2 Receptors J. Am. Soc. Nephrol., December 1, 2003; 14(12): 3061 - 3071. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mori, M. Tanaka, D. Nanba, E. Nishiwaki, H. Ishiguro, S. Higashiyama, and N. Matsuura PACSIN3 Binds ADAM12/Meltrin {alpha} and Up-regulates Ectodomain Shedding of Heparin-binding Epidermal Growth Factor-like Growth Factor J. Biol. Chem., November 14, 2003; 278(46): 46029 - 46034. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Uemura, H. Ishiguro, N. Nakaigawa, Y. Nagashima, Y. Miyoshi, K. Fujinami, A. Sakaguchi, and Y. Kubota Angiotensin II receptor blocker shows antiproliferative activity in prostate cancer cells: A possibility of tyrosine kinase inhibitor of growth factor Mol. Cancer Ther., November 1, 2003; 2(11): 1139 - 1147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sarlos, B. Rizkalla, C. J. Moravski, Z. Cao, M. E. Cooper, and J. L. Wilkinson-Berka Retinal Angiogenesis Is Mediated by an Interaction between the Angiotensin Type 2 Receptor, VEGF, and Angiopoietin Am. J. Pathol., September 1, 2003; 163(3): 879 - 887. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Ahmed, D. Gesty-Palmer, M. K. Drezner, and L. M. Luttrell Transactivation of the Epidermal Growth Factor Receptor Mediates Parathyroid Hormone and Prostaglandin F2{alpha}-Stimulated Mitogen-Activated Protein Kinase Activation in Cultured Transgenic Murine Osteoblasts Mol. Endocrinol., August 1, 2003; 17(8): 1607 - 1621. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Takenobu, A. Yamazaki, M. Hirata, T. Umata, and E. Mekada The Stress- and Inflammatory Cytokine-induced Ectodomain Shedding of Heparin-binding Epidermal Growth Factor-like Growth Factor Is Mediated by p38 MAPK, Distinct from the 12-O-Tetradecanoylphorbol-13-acetate- and Lysophosphatidic Acid-induced Signaling Cascades J. Biol. Chem., May 2, 2003; 278(19): 17255 - 17262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. de Boer, Y. M. Pinto, A. J.H. Suurmeijer, S. Pokharel, E. Scholtens, M. Humler, J. M. Saavedra, F. Boomsma, W. H. van Gilst, and D. J. van Veldhuisen Increased expression of cardiac angiotensin II type 1 (AT1) receptors decreases myocardial microvessel density after experimental myocardial infarction Cardiovasc Res, February 1, 2003; 57(2): 434 - 442. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Brutsaert Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity Physiol Rev, January 1, 2003; 83(1): 59 - 115. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Werner and G. Nickenig AT1 receptors in atherosclerosis: biological effects including growth, angiogenesis, and apoptosis Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A9 - A13. [Abstract] [PDF]
|
|
|
|
 |
|
 J.-S. Silvestre, R. Tamarat, T. Senbonmatsu, T. Icchiki, T. Ebrahimian, M. Iglarz, S. Besnard, M. Duriez, T. Inagami, and B. I. Levy Antiangiogenic Effect of Angiotensin II Type 2 Receptor in Ischemia-Induced Angiogenesis in Mice Hindlimb Circ. Res., May 31, 2002; 90(10): 1072 - 1079. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Ando, T. Nagasaka, M. Nomura, S.-I. Tsukahara, Y. Kotani, S. Toda, Y. Murata, A. Itakura, and S. Mizutani Premenstrual Disappearance of Aminopeptidase A in Endometrial Stromal Cells around Endometrial Spiral Arteries/Arterioles during the Decidual Change J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2303 - 2309. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Moll, M. Weick, I. Milenkovic, H. Kodal, A. Reichenbach, and A. Bringmann P2Y Receptor-Mediated Stimulation of Muller Glial DNA Synthesis Invest. Ophthalmol. Vis. Sci., March 1, 2002; 43(3): 766 - 773. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Tamarat, J.-S. Silvestre, N. Kubis, J. Benessiano, M. Duriez, M. deGasparo, D. Henrion, and B. I. Levy Endothelial Nitric Oxide Synthase Lies Downstream From Angiotensin II-Induced Angiogenesis in Ischemic Hindlimb Hypertension, March 1, 2002; 39(3): 830 - 835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. G. Thomas, Y. Brandenburger, D. J. Autelitano, T. Pham, H. Qian, and R. D. Hannan Adenoviral-Directed Expression of the Type 1A Angiotensin Receptor Promotes Cardiomyocyte Hypertrophy via Transactivation of the Epidermal Growth Factor Receptor Circ. Res., February 8, 2002; 90(2): 135 - 142. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Keates, S. Sougioultzis, A. C. Keates, D. Zhao, R. M. Peek Jr., L. M. Shaw, and C. P. Kelly cag+ Helicobacter pylori Induce Transactivation of the Epidermal Growth Factor Receptor in AGS Gastric Epithelial Cells J. Biol. Chem., December 14, 2001; 276(51): 48127 - 48134. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kamihata, H. Matsubara, T. Nishiue, S. Fujiyama, Y. Tsutsumi, R. Ozono, H. Masaki, Y. Mori, O. Iba, E. Tateishi, et al. Implantation of Bone Marrow Mononuclear Cells Into Ischemic Myocardium Enhances Collateral Perfusion and Regional Function via Side Supply of Angioblasts, Angiogenic Ligands, and Cytokines Circulation, August 28, 2001; 104(9): 1046 - 1052. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Schneider and B. H. Lorell AT2, Judgment Day: Which Angiotensin Receptor Is the Culprit in Cardiac Hypertrophy? Circulation, July 17, 2001; 104(3): 247 - 248. [Full Text] [PDF]
|
|
|
|
|
|
R. Ginnan and H. A. Singer CaM kinase II-dependent activation of tyrosine kinases and ERK1/2 in vascular smooth muscle Am J Physiol Cell Physiol, April 1, 2002; 282(4): C754 - C761. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. G. Thomas, Y. Brandenburger, D. J. Autelitano, T. Pham, H. Qian, and R. D. Hannan Adenoviral-Directed Expression of the Type 1A Angiotensin Receptor Promotes Cardiomyocyte Hypertrophy via Transactivation of the Epidermal Growth Factor Receptor Circ. Res., February 8, 2002; 90(2): 135 - 142. [Abstract] [Full Text] [PDF]
|
|