Regulation of Vascular Endothelial Growth Factor Expression and Vascularization in the Myocardium by Insulin Receptor and PI3K/Akt Pathways in Insulin Resistance and Ischemia
Abstract
Objective— This study characterized the role of insulin receptors and resistance on vascular endothelial growth factor (VEGF) expression and myocardial vascularization in physiological conditions and after ischemia. Methods and Results— Cardiac microvascular density was reduced by 30% in insulin-resistant Zucker fatty rats versus lean controls. This was associated with a parallel 40% inhibition of insulin-stimulated activation of both Akt and VEGF expression in the myocardium and cardiomyocytes. In contrast, the activation of Erk1/2 by insulin remained unchanged. In cultured cardiomyocytes, insulin or insulin-like growth factor (IGF)-1 increased VEGF mRNA and protein expression by 2-fold. Inhibition of PI3K/Akt, especially Akt2-mediated cascades but not the Ras/MEK/Erk pathway, using chemical inhibitors, dominant negative adenoviral constructs, or siRNA approaches suppressed VEGF mRNA expression by insulin. Ventricular tissues from muscle insulin receptor knockout (MIRKO) mice, which lack insulin receptors in the myocardium, have significant reductions in insulin but not IGF-1 signaling, VEGF expression, and vascular density before and after ischemia versus controls. Conclusions— Insulin regulates VEGF gene expression and vascularization in the myocardium specifically via insulin receptors and the activation of PI3K/Akt pathway. Selective inhibition of this pathway may lead to the decreases in VEGF expression and capillary density in the myocardium of patients with insulin resistance.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Impaired angiogenic signaling was confirmed in hearts of Zucker rats and in muscle-restricted insulin receptor KO mice lacking myocardial insulin receptor expression.
“Impaired angiogenic signaling was also independently confirmed in the hearts of Zucker rats and in muscle-restricted insulin receptor KO mice that also lack insulin receptor expression in the myocardium (133, 349).”
From Cardiac remodeling in obesity (2008) · cites this paper as [133]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The biology of VEGF and its receptors
Ferrara, N., Gerber, H.-P., & LeCouter, J. (2003) · Nature Medicine · doi:10.1038/nm0603-669 · Cited by 9,591 · see citing works
Haffner, S. M., Lehto, S., Rönnemaa, T., Pyörälä, K., & Laakso, M. (1998) · New England Journal of Medicine · doi:10.1056/nejm199807233390404 · Cited by 7,000 · see citing works
A central role for JNK in obesity and insulin resistance
Hirosumi, J., Tuncman, G., Chang, L., Görgün, C. Z., Uysal, K. T., Maeda, K., Karin, M., & Hotamisligil, G. S. (2002) · Nature · doi:10.1038/nature01137 · Cited by 3,359 · see citing works
Brüning, J. C., Michael, M. D., Winnay, J. N., Hayashi, T., Hörsch, D., Accili, D., Goodyear, L. J., & Kahn, C. R. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80155-0 · Cited by 1,183 · see citing works
Self-citationCusi, K., Maezono, K., Osman, A., Pendergrass, M., Patti, M. E., Pratipanawatr, T., DeFronzo, R. A., Kahn, C. R., & Mandarino, L. J. (2000) · Journal of Clinical Investigation · doi:10.1172/jci7535 · Cited by 1,139 · see citing works
Self-citationKuboki, K., Jiang, Z. Y., Takahara, N., Ha, S. W., Igarashi, M., Yamauchi, T., Feener, E. P., Herbert, T. P., Rhodes, C. J., & King, G. L. (2000) · Circulation · doi:10.1161/01.cir.101.6.676 · Cited by 636 · see citing works
Self-citationEffect of Diabetes Mellitus on Formation of Coronary Collateral Vessels
Abacı, A., Oğuzhan, A., Kahraman, S., Eryol, N. K., Ünal, S., Arınç, H., & Ergin, A. (1999) · Circulation · doi:10.1161/01.cir.99.17.2239 · Cited by 626 · see citing works
Jiang, Z. Y., Lin, Y.-W., Clemont, A., Feener, E. P., Hein, K. D., Igarashi, M., Yamauchi, T., White, M. F., & King, G. L. (1999) · Journal of Clinical Investigation · doi:10.1172/jci5971 · Cited by 604 · see citing works
Self-citationXia, P., Inoguchi, T., Kern, T. S., Engerman, R. L., Oates, P. J., & King, G. L. (1994) · Diabetes · doi:10.2337/diab.43.9.1122 · Cited by 476 · see citing works
Self-citationProtein Kinase Bα/Akt1 Regulates Placental Development and Fetal Growth
Yang, Z.-Z., Tschopp, O., Hemmings-Mieszczak, M., Feng, J., Brodbeck, D., Perentes, E., & Hemmings, B. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m302847200 · Cited by 384 · see citing works
Jiang, Z. Y., Zhou, Q. L., Coleman, K. A., Chouinard, M., Boese, Q., & Czech, M. P. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1332633100 · Cited by 378 · see citing works
Giordano, F. J., Gerber, H., Williams, S., van Bruggen, N., Bunting, S., Ruiz‐Lozano, P., Gu, Y., Nath, A. K., Huang, Y., Hickey, R. P., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.091415198 · Cited by 370 · see citing works
Ueki, K., Yamamoto‐Honda, R., Kaburagi, Y., Yamauchi, T., Tobe, K., Burgering, B. M. T., Coffer, P. J., Komuro, I., Akanuma, Y., Yazaki, Y., et al. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.9.5315 · Cited by 356 · see citing works
Self-citationChou, E. L., Suzuma, I., Way, K. J., Opland, D. M., Clermont, A. C., Naruse, K., Suzuma, K., Bowling, N. L., Vlahos, C. J., Aiello, L. P., et al. (2002) · Circulation · doi:10.1161/hc0302.102143 · Cited by 337 · see citing works
Self-citationJain, M., Dersimonian, H., Brenner, D. A., et al. (2001) · Circulation · doi:10.1161/01.cir.103.14.1920 · Cited by 294 · see citing works
Yoon, Y., Uchida, S., Masuo, O., Cejna, M., Park, J., Gwon, H., Kirchmair, R., Bahlman, F., Walter, D. H., Curry, C., et al. (2005) · Circulation · doi:10.1161/01.cir.0000162472.52990.36 · Cited by 287 · see citing works
Metabolic disturbances in diabetic cardiomyopathy.
Rodrigues, B. B., Cam, M. C., & McNeill, J. H. (1998) · PubMed · Cited by 248 · see citing works
Suzuma, K., Naruse, K., Suzuma, I., Takahara, N., Ueki, K., Aiello, L. P., & King, G. L. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m006509200 · Cited by 240 · see citing works
Self-citationPoulaki, V., Qin, W., Joussen, A. M., Hurlbut, P., Wiegand, S. J., Rudge, J. S., Yancopoulos, G. D., & Adamis, A. P. (2002) · Journal of Clinical Investigation · doi:10.1172/jci13776 · Cited by 222 · see citing works
Miele, C., Rochford, J. J., Filippa, N., Giorgetti‐Peraldi, S., & OBBERGHEN, E. V. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m000805200 · Cited by 216 · see citing works
Metabolic disturbances in diabetic cardiomyopathy
Rodrigues, B. B., Cam, M. C., & McNeill, J. H. (1998) · Molecular and Cellular Biochemistry · doi:10.1023/a:1006882805197 · Cited by 197 · see citing works
Poulaki, V., Qin, W., Joussen, A. M., Hurlbut, P., Wiegand, S. J., Rudge, J. S., Yancopoulos, G. D., & Adamis, A. P. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0213776 · Cited by 190 · see citing works
Lindsey, M. L., Gannon, J., Aikawa, M., Schöen, F. J., Aikawa, E. R., Lopresti‐Morrow, L., Crawford, J., Black, S. C., Libby, P., Mitchell, P. G., et al. (2002) · Circulation · doi:10.1161/hc0602.103674 · Cited by 186 · see citing works
Myogenic Akt Signaling Regulates Blood Vessel Recruitment during Myofiber Growth
Takahashi, A., Kureishi, Y., Jiang, Y., Luo, Z., Guo, K. Y., Mukhopadhyay, D., Ivashchenko, Y., Branellec, D., & Walsh, K. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.13.4803-4814.2002 · Cited by 159 · see citing works
Human coronary microvessels in diabetes and ischaemia. Morphometric study of autopsy material
Yarom, R., Zirkin, H. J., Stämmler, G., & Rose, A. G. (1992) · The Journal of Pathology · doi:10.1002/path.1711660308 · Cited by 138 · see citing works
Jiang, Z. Y., He, Z., King, B. L., Kuroki, T., Opland, D. M., Suzuma, K., Suzuma, I., Ueki, K., Kulkarni, R., Kahn, C. R., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m303314200 · Cited by 110 · see citing works
Self-citationSurfing the insulin signaling web
OBBERGHEN, E. V., Baron, V. T., Delahaye, L., Emanuelli, B., Filippa, N., Giorgetti‐Peraldi, S., Lebrun, P., Mothe‐Satney, I., Peraldi, P., Rocchi, S., et al. (2001) · European Journal of Clinical Investigation · doi:10.1046/j.1365-2362.2001.00896.x · Cited by 106 · see citing works
Prevention Conference VI: Diabetes and Cardiovascular Disease
Smith, S. C., Faxon, D. P., Cascio, W. E., Schaff, H. V., Gardner, T. J., Jacobs, A. K., Nissen, S. E., & Stouffer, R. (2002) · Circulation · doi:10.1161/01.cir.0000013957.30622.05 · Cited by 95 · see citing works
Shaw, S., Wang, X., Redd, H., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305008200 · Cited by 80 · see citing works
Angiotensin-Converting enzyme inhibition and angiogenesis in myocardium of obese Zucker rats
Toblli, J. (2004) · American Journal of Hypertension · doi:10.1016/j.amjhyper.2003.10.006 · Cited by 71 · see citing works
Carvalheira, J. B. C., Calegari, V. C., Zecchin, H. G., Nadruz, W., Guimarães, R. B., Ribeiro, E. B., Franchini, K. G., Velloso, L. A., & Saad, M. J. A. (2003) · Endocrinology · doi:10.1210/en.2003-0788 · Cited by 59 · see citing works
Cardiovascular protective role of a low-dose antihypertensive combination in obese Zucker rats
Toblli, J. E., DeRosa, G., Rivas, C., Cao, G., Piorno, P., Pagano, P., & Forcada, P. J. (2003) · Journal of Hypertension · doi:10.1097/00004872-200303000-00028 · Cited by 29 · see citing works
Satoh, N., Suter, T. M., Liao, R., et al. (2000) · Circulation · doi:10.1161/01.cir.102.18.2249 · Cited by 23 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Abel, E. D., Litwin, S. E., & Sweeney, G. (2008) · Physiological Reviews · doi:10.1152/physrev.00017.2007 · Cited by 736 · see citing works
Insulin says NO to cardiovascular disease
Yu, Q., Gao, F., & Ma, X. L. (2011) · Cardiovascular Research · doi:10.1093/cvr/cvq349 · Cited by 172 · see citing works
- Authors
- He, Z., Opland, D. M., Way, K. J., Ueki, K., Bodyak, N., Kang, P. M., Izumo, S., Kulkarni, R. N., Wang, B., Liao, R., Kahn, C. R., & King, G. L.
- Affiliations
- Boston University (US)
- ORCID
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2006-04
- Volume
- 26
- Issue
- 4
- Pages
- 787-793
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- OpenAlex
- W2141397996
- Cited by
- 94
- References
- 33
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 5 · 2022: 1 · 2021: 6 · 2020: 5 · 2019: 5 · 2018: 3 · 2017: 3 · 2016: 5 · 2015: 4 · 2014: 2 · 2013: 5 · 2012: 3
- FWCI
- 3.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01dk059725-05)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK 53105, R01DK053105, DK02885-03, K08DK002885, R01 DK59725)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- vascular endothelial growth factor, insulin resistance, myocardial vascularization, insulin receptor, PI3K/Akt signaling, AKT2, cardiomyocytes, myocardial ischemia, insulin-like growth factor I, ERK signaling, Zucker fatty rats
- MeSH terms
- Wortmannin, Phosphoinositide-3 Kinase Inhibitors, Androstadienes, Animals, Cells, Cultured, Coronary Vessels, Flavonoids, Humans, Insulin, Insulin Resistance, Male, Neovascularization, Pathologic, Rats, Zucker, Receptor, Insulin, Signal Transduction, Myocardial Ischemia, Phosphatidylinositol 3-Kinases, Myocytes, Cardiac, Vascular Endothelial Growth Factor A, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Mice, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
