Circulation. 2002;105:373-379
doi: 10.1161/hc0302.102143
doi: 10.1161/hc0302.102143
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2002;105:373.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Decreased Cardiac Expression of Vascular Endothelial Growth Factor and Its Receptors in Insulin-Resistant and Diabetic States
A Possible Explanation for Impaired Collateral Formation in Cardiac Tissue
From the Research Division (E.C., I.S., K.J.W., D.O., K.N., K.S., L.P.A., G.L.K.) and Beetham Eye Institute (A.C.C., L.P.A.), Joslin Diabetes Center, Boston, Mass; the Departments of Medicine (G.L.K.) and Ophthalmology (L.P.A.), Harvard Medical School, Boston, Mass; and Lilly Research Laboratories (N.L.B., C.J.V.), Indianapolis, Ind.
Correspondence to George L. King, MD, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail george.king{at}joslin.harvard.edu
Background— Inadequate angiogenic response to ischemia in the myocardium of diabetic patients could result in poor collateral formation. Yet, excessive neovascularization in the retina causes proliferative diabetic retinopathy. Since vascular endothelial growth factor (VEGF) is the major angiogenic factor expressed in response to hypoxia, we have characterized expression of VEGF and its receptors in retina, renal glomeruli, aorta, and myocardium in insulin-resistant and diabetic states.
Methods and Results— The expression of mRNA and protein for VEGF and its receptors, VEGF-R1 and VEGF-R2, in the myocardium was decreased significantly by 40% to 70% in both diabetic and insulin-resistant nondiabetic rats. Twofold reductions in VEGF and VEGF-R2 were observed in ventricles from diabetic patients compared with nondiabetic donors. In contrast, expression of VEGF and its receptors were increased 2-fold in retina and glomeruli from diabetic or insulin-resistant rats. Insulin treatment of diabetic rats normalized changes in both cardiac and microvascular tissues. Insulin increased VEGF mRNA expression in cultured rat neonatal cardiac myocytes.
Conclusions— The results documented for the first time that differential regulation of VEGF and its receptors exist between microvascular and cardiac tissues, which can be regulated by insulin. These results provide a potential explanation for concomitant capillary leakage and neovascularization in the retina and inadequate collateral formation in the myocardium of insulin-resistant and diabetic patients.
Key Words: growth substances • diabetes mellitus • myocardium • collateral circulation • insulin
This article has been cited by other articles:
 |
|
 |
|
  C. Whee Park, H. Wook Kim, J. Hee Lim, K. Dong Yoo, S. Chung, S. Joon Shin, H. Wha Chung, S. Ju Lee, C.-B. Chae, Y.-S. Kim, et al. Vascular Endothelial Growth Factor Inhibition by dRK6 Causes Endothelial Apoptosis, Fibrosis, and Inflammation in the Heart via the Akt/eNOS Axis in db/db Mice Diabetes, November 1, 2009; 58(11): 2666 - 2676. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Thangarajah, D. Yao, E. I. Chang, Y. Shi, L. Jazayeri, I. N. Vial, R. D. Galiano, X.-L. Du, R. Grogan, M. G. Galvez, et al. The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues PNAS, August 11, 2009; 106(32): 13505 - 13510. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Han, R. Baliga, H. Huang, P. J. Giannone, and J. A. Bauer Decreased cardiac expression of vascular endothelial growth factor and redox imbalance in murine diabetic cardiomyopathy Am J Physiol Heart Circ Physiol, August 1, 2009; 297(2): H829 - H835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nakagawa, T. Kosugi, M. Haneda, C. J. Rivard, and D. A. Long Abnormal Angiogenesis in Diabetic Nephropathy Diabetes, July 1, 2009; 58(7): 1471 - 1478. [Full Text] [PDF]
|
|
|
|
 |
|
 J.-X. Chen and A. Stinnett Disruption of Ang-1/Tie-2 Signaling Contributes to the Impaired Myocardial Vascular Maturation and Angiogenesis in Type II Diabetic Mice Arterioscler Thromb Vasc Biol, September 1, 2008; 28(9): 1606 - 1613. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Rask-Madsen and G. L. King Differential Regulation of VEGF Signaling by PKC-{alpha} and PKC-{epsilon} in Endothelial Cells Arterioscler Thromb Vasc Biol, May 1, 2008; 28(5): 919 - 924. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Rask-Madsen and G. L. King More Sugar, Less Blood Vessels: Another Piece in the Puzzle of Increased Cardiovascular Risk in Diabetes Arterioscler Thromb Vasc Biol, April 1, 2008; 28(4): 608 - 610. [Full Text] [PDF]
|
|
|
|
 |
|
 E. D. Abel, S. E. Litwin, and G. Sweeney Cardiac Remodeling in Obesity Physiol Rev, April 1, 2008; 88(2): 389 - 419. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Siebert, M. Reiwer-Gostomska, Z. Babinska, J. Mysliwska, A. Mysliwski, E. Skopinska-Rozewska, E. Sommer, and P. Skopinski Low Serum Angiogenin Concentrations in Patients With Type 2 Diabetes Diabetes Care, December 1, 2007; 30(12): 3086 - 3087. [Full Text] [PDF]
|
|
|
|
 |
|
 H. Masuyama, H. Nakatsukasa, N. Takamoto, and Y. Hiramatsu Correlation between Soluble Endoglin, Vascular Endothelial Growth Factor Receptor-1, and Adipocytokines in Preeclampsia J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2672 - 2679. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Arikawa, R. C.W. Ma, K. Isshiki, I. Luptak, Z. He, Y. Yasuda, Y. Maeno, M. E. Patti, G. C. Weir, R. A. Harris, et al. Effects of Insulin Replacements, Inhibitors of Angiotensin, and PKC{beta}'s Actions to Normalize Cardiac Gene Expression and Fuel Metabolism in Diabetic Rats Diabetes, May 1, 2007; 56(5): 1410 - 1420. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Jesmin, S. Zaedi, N. Shimojo, M. Iemitsu, K. Masuzawa, N. Yamaguchi, C. N. Mowa, S. Maeda, Y. Hattori, and T. Miyauchi Endothelin antagonism normalizes VEGF signaling and cardiac function in STZ-induced diabetic rat hearts Am J Physiol Endocrinol Metab, April 1, 2007; 292(4): E1030 - E1040. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Li, S. Hazarika, D. Xie, A. M. Pippen, C. D. Kontos, and B. H. Annex In Mice With Type 2 Diabetes, a Vascular Endothelial Growth Factor (VEGF)-Activating Transcription Factor Modulates VEGF Signaling and Induces Therapeutic Angiogenesis After Hindlimb Ischemia Diabetes, March 1, 2007; 56(3): 656 - 665. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. W.Y. Chung, Y. N. Hsiang, L. A. Matzke, B. M. McManus, C. van Breemen, and E. B. Okon Reduced Expression of Vascular Endothelial Growth Factor Paralleled With the Increased Angiostatin Expression Resulting From the Upregulated Activities of Matrix Metalloproteinase-2 and -9 in Human Type 2 Diabetic Arterial Vasculature Circ. Res., July 21, 2006; 99(2): 140 - 148. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Kivela, M. Silvennoinen, A.-M. Touvra, T. M. Lehti, H. Kainulainen, and V. Vihko Effects of experimental type 1 diabetes and exercise training on angiogenic gene expression and capillarization in skeletal muscle FASEB J, July 1, 2006; 20(9): 1570 - 1572. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Jesmin, S. Zaedi, N. Yamaguchi, S. Maeda, N. Shimojo, K. Masuzawa, I. Yamaguchi, K. Goto, and T. Miyauchi Differential effects of selective endothelin type a receptor antagonist on the gene expression of vascular endothelial growth factor and its receptors in streptozotocin-induced diabetic heart. Experimental Biology and Medicine, June 1, 2006; 231(6): 902 - 906. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. B. Sotiropoulos, A. Clermont, Y. Yasuda, C. Rask-Madsen, M. Mastumoto, J. Takahashi, K. Della Vecchia, T. Kondo, L. P. Aiello, and G. L. King Adipose-specific effect of rosiglitazone on vascular permeability and protein kinase C activation: novel mechanism for PPAR{gamma} agonist's effects on edema and weight gain FASEB J, June 1, 2006; 20(8): 1203 - 1205. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M Safley, J. A House, B. D Rutherford, and S. P Marso Success rates of percutaneous coronary intervention of chronic total occlusions and long-term survival in patients with diabetes mellitus Diabetes and Vascular Disease Research, May 1, 2006; 3(1): 45 - 51. [Abstract] [PDF]
|
|
|
|
|
|
Z. He, D. M. Opland, K. J. Way, K. Ueki, N. Bodyak, P. M. Kang, S. Izumo, R. N. Kulkarni, B. Wang, R. Liao, et al. Regulation of Vascular Endothelial Growth Factor Expression and Vascularization in the Myocardium by Insulin Receptor and PI3K/Akt Pathways in Insulin Resistance and Ischemia Arterioscler Thromb Vasc Biol, April 1, 2006; 26(4): 787 - 793. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. E. Gilbert, K. Connelly, D. J. Kelly, C. A. Pollock, and H. Krum Heart Failure and Nephropathy: Catastrophic and Interrelated Complications of Diabetes Clin. J. Am. Soc. Nephrol., March 1, 2006; 1(2): 193 - 208. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Oltmanns, H. Gehring, S. Rudolf, B. Schultes, C. Hackenberg, U. Schweiger, J. Born, H. L. Fehm, and A. Peters Acute hypoxia decreases plasma VEGF concentration in healthy humans Am J Physiol Endocrinol Metab, March 1, 2006; 290(3): E434 - E439. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. C. Sasso, D. Torella, O. Carbonara, G. M. Ellison, M. Torella, M. Scardone, C. Marra, R. Nasti, R. Marfella, D. Cozzolino, et al. Increased Vascular Endothelial Growth Factor Expression But Impaired Vascular Endothelial Growth Factor Receptor Signaling in the Myocardium of Type 2 Diabetic Patients With Chronic Coronary Heart Disease J. Am. Coll. Cardiol., September 6, 2005; 46(5): 827 - 834. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Simons Angiogenesis, Arteriogenesis, and Diabetes: Paradigm Reassessed? J. Am. Coll. Cardiol., September 6, 2005; 46(5): 835 - 837. [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-s. Yoon, S. Uchida, O. Masuo, M. Cejna, J.-S. Park, H.-c. Gwon, R. Kirchmair, F. Bahlman, D. Walter, C. Curry, et al. Progressive Attenuation of Myocardial Vascular Endothelial Growth Factor Expression Is a Seminal Event in Diabetic Cardiomyopathy: Restoration of Microvascular Homeostasis and Recovery of Cardiac Function in Diabetic Cardiomyopathy After Replenishment of Local Vascular Endothelial Growth Factor Circulation, April 26, 2005; 111(16): 2073 - 2085. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. He, K. J. Way, E. Arikawa, E. Chou, D. M. Opland, A. Clermont, K. Isshiki, R. C. W. Ma, J. A. Scott, F. J. Schoen, et al. Differential Regulation of Angiotensin II-induced Expression of Connective Tissue Growth Factor by Protein Kinase C Isoforms in the Myocardium J. Biol. Chem., April 22, 2005; 280(16): 15719 - 15726. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P Marso, J. W Murphy, J. A House, D. M Safley, and W. S Harris Metabolic syndrome-mediated inflammation following elective percutaneous coronary intervention Diabetes and Vascular Disease Research, February 1, 2005; 2(1): 31 - 36. [Abstract] [PDF]
|
|
|
|
 |
|
 T. P. Gavin, H. W. Stallings III, K. A. Zwetsloot, L. M. Westerkamp, N. A. Ryan, R. A. Moore, W. E. Pofahl, and R. C. Hickner Lower capillary density but no difference in VEGF expression in obese vs. lean young skeletal muscle in humans J Appl Physiol, January 1, 2005; 98(1): 315 - 321. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Wolf, C. A. Hubel, C. Lam, M. Sampson, J. L. Ecker, R. B. Ness, A. Rajakumar, A. Daftary, A. S. M. Shakir, E. W. Seely, et al. Preeclampsia and Future Cardiovascular Disease: Potential Role of Altered Angiogenesis and Insulin Resistance J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6239 - 6243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. S. Werner, E. Jandt, A. Krack, G. Schwarz, O. Mutschke, F. Kuethe, M. Ferrari, and H. R. Figulla Growth Factors in the Collateral Circulation of Chronic Total Coronary Occlusions: Relation to Duration of Occlusion and Collateral Function Circulation, October 5, 2004; 110(14): 1940 - 1945. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. J. Rowe The Case for a Subcutaneous Magnesium Product and Delivery Device for Space Missions J. Am. Coll. Nutr., October 1, 2004; 23(5): 525S - 528S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Marfella, K. Esposito, F. Nappo, M. Siniscalchi, F. C. Sasso, M. Portoghese, M. Pia Di Marino, A. Baldi, S. Cuzzocrea, C. Di Filippo, et al. Expression of Angiogenic Factors During Acute Coronary Syndromes in Human Type 2 Diabetes Diabetes, September 1, 2004; 53(9): 2383 - 2391. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. He and G. L. King Protein Kinase C{beta} Isoform Inhibitors: A New Treatment for Diabetic Cardiovascular Diseases Circulation, July 6, 2004; 110(1): 7 - 9. [Full Text] [PDF]
|
|
|
|
 |
|
 R. Thadhani, J. L. Ecker, W. P. Mutter, M. Wolf, K. V. Smirnakis, V. P. Sukhatme, R. J. Levine, and S. A. Karumanchi Insulin Resistance and Alterations in Angiogenesis: Additive Insults That May Lead to Preeclampsia Hypertension, May 1, 2004; 43(5): 988 - 992. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Larger, M. Marre, P. Corvol, and J.-M. Gasc Hyperglycemia-Induced Defects in Angiogenesis in the Chicken Chorioallantoic Membrane Model Diabetes, March 1, 2004; 53(3): 752 - 761. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Y. Jiang, Z. He, B. L. King, T. Kuroki, D. M. Opland, K. Suzuma, I. Suzuma, K. Ueki, R. N. Kulkarni, C. R. Kahn, et al. Characterization of Multiple Signaling Pathways of Insulin in the Regulation of Vascular Endothelial Growth Factor Expression in Vascular Cells and Angiogenesis J. Biol. Chem., August 22, 2003; 278(34): 31964 - 31971. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Hu, D. Zhang, L. Swenson, G. Chakrabarti, E. D. Abel, and S. E. Litwin Minimally invasive aortic banding in mice: effects of altered cardiomyocyte insulin signaling during pressure overload Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H1261 - H1269. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. S. Werner, B. M. Richartz, S. Heinke, M. Ferrari, and H. R. Figulla Impaired acute collateral recruitment as a possible mechanism for increased cardiac adverse events in patients with diabetes mellitus Eur. Heart J., June 2, 2003; 24(12): 1134 - 1142. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yokota, R. C. Ma, J.-Y. Park, K. Isshiki, K. B. Sotiropoulos, R. K. Rauniyar, K. E. Bornfeldt, and G. L. King Role of Protein Kinase C on the Expression of Platelet-Derived Growth Factor and Endothelin-1 in the Retina of Diabetic Rats and Cultured Retinal Capillary Pericytes Diabetes, March 1, 2003; 52(3): 838 - 845. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. He, C. Rask-Madsen, and G.L. King Mechanisms of cardiovascular complications in diabetes and potential new pharmacological therapies Eur. Heart J. Suppl., January 1, 2003; 5(suppl_B): B51 - B57. [Abstract] [PDF]
|
|
|
|
|
|
S. Jesmin, Y. Hattori, I. Sakuma, C. N. Mowa, and A. Kitabatake Role of ANG II in coronary capillary angiogenesis at the insulin-resistant stage of a NIDDM rat model Am J Physiol Heart Circ Physiol, October 1, 2002; 283 (4): H1387 - H1397. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Nakagami, R. Morishita, K. Yamamoto, Y. Taniyama, M. Aoki, K. Yamasaki, K. Matsumoto, T. Nakamura, Y. Kaneda, and T. Ogihara Hepatocyte Growth Factor Prevents Endothelial Cell Death Through Inhibition of bax Translocation From Cytosol to Mitochondrial Membrane Diabetes, August 1, 2002; 51(8): 2604 - 2611. [Abstract] [Full Text] [PDF]
|
|