Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Jul 1;100(1):18–24. doi: 10.1172/JCI119510

Stretch-induced VEGF expression in the heart.

J Li 1, T Hampton 1, J P Morgan 1, M Simons 1
PMCID: PMC508160  PMID: 9202052

Abstract

Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen involved in vascular development and angiogenesis. Recently we have observed increased VEGF expression in the normal myocardium after myocardial infarction in a rat heart. This study was designed to explore the mechanism responsible for this increase in VEGF expression. Induction of myocardial stretch in an isolated perfused Langendorff preparation by inflation of an intraventricular balloon to an end-diastolic load of 35 mmHg for 30 min resulted in a nearly sixfold increase in VEGF message level not only in the chamber subjected to stretch (left ventricle) but also in the unstretched right ventricle, thus raising the possibility of a soluble factor mediating stretch- induced induction of VEGF expression. This was further confirmed by demonstrating that coronary venous effluent collected from the stretched heart and used to perfuse isolated hearts in which no balloon was present was able to induce VEGF expression in these normal hearts. Inhibition of TGF-beta activity using a neutralizing antibody, but not antagonists/inhibitors of endothelin and angiotensin II, eliminated stretch-induced increase in VEGF expression. Staurosporine, a protein kinase C inhibitor, also blocked stretch-induced increase of VEGF expression. Measurement of TGF-beta concentration in the perfusate demonstrated increased amounts of the cytokine after myocardial stretch, and addition of TGF-beta protein to the perfusion buffer resulted in increased VEGF expression in control hearts. These results suggest that stretch-induced increase of VEGF expression in the heart is mediated at least in part by TGF-beta.

Full Text

The Full Text of this article is available as a PDF (542.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aiello L. P., Avery R. L., Arrigg P. G., Keyt B. A., Jampel H. D., Shah S. T., Pasquale L. R., Thieme H., Iwamoto M. A., Park J. E. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994 Dec 1;331(22):1480–1487. doi: 10.1056/NEJM199412013312203. [DOI] [PubMed] [Google Scholar]
  2. Berse B., Brown L. F., Van de Water L., Dvorak H. F., Senger D. R. Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell. 1992 Feb;3(2):211–220. doi: 10.1091/mbc.3.2.211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brogi E., Wu T., Namiki A., Isner J. M. Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, whereas hypoxia upregulates VEGF expression only. Circulation. 1994 Aug;90(2):649–652. doi: 10.1161/01.cir.90.2.649. [DOI] [PubMed] [Google Scholar]
  4. Brown L. F., Dubin D., Lavigne L., Logan B., Dvorak H. F., Van de Water L. Macrophages and fibroblasts express embryonic fibronectins during cutaneous wound healing. Am J Pathol. 1993 Mar;142(3):793–801. [PMC free article] [PubMed] [Google Scholar]
  5. Carmeliet P., Ferreira V., Breier G., Pollefeyt S., Kieckens L., Gertsenstein M., Fahrig M., Vandenhoeck A., Harpal K., Eberhardt C. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996 Apr 4;380(6573):435–439. doi: 10.1038/380435a0. [DOI] [PubMed] [Google Scholar]
  6. Cohen T., Nahari D., Cerem L. W., Neufeld G., Levi B. Z. Interleukin 6 induces the expression of vascular endothelial growth factor. J Biol Chem. 1996 Jan 12;271(2):736–741. doi: 10.1074/jbc.271.2.736. [DOI] [PubMed] [Google Scholar]
  7. Dvorak H. F., Brown L. F., Detmar M., Dvorak A. M. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol. 1995 May;146(5):1029–1039. [PMC free article] [PubMed] [Google Scholar]
  8. Ferrara N., Carver-Moore K., Chen H., Dowd M., Lu L., O'Shea K. S., Powell-Braxton L., Hillan K. J., Moore M. W. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996 Apr 4;380(6573):439–442. doi: 10.1038/380439a0. [DOI] [PubMed] [Google Scholar]
  9. Ferrara N., Heinsohn H., Walder C. E., Bunting S., Thomas G. R. The regulation of blood vessel growth by vascular endothelial growth factor. Ann N Y Acad Sci. 1995 Mar 27;752:246–256. doi: 10.1111/j.1749-6632.1995.tb17435.x. [DOI] [PubMed] [Google Scholar]
  10. Ferrara N., Houck K., Jakeman L., Leung D. W. Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev. 1992 Feb;13(1):18–32. doi: 10.1210/edrv-13-1-18. [DOI] [PubMed] [Google Scholar]
  11. Finkenzeller G., Marmé D., Weich H. A., Hug H. Platelet-derived growth factor-induced transcription of the vascular endothelial growth factor gene is mediated by protein kinase C. Cancer Res. 1992 Sep 1;52(17):4821–4823. [PubMed] [Google Scholar]
  12. Fong G. H., Rossant J., Gertsenstein M., Breitman M. L. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature. 1995 Jul 6;376(6535):66–70. doi: 10.1038/376066a0. [DOI] [PubMed] [Google Scholar]
  13. Grandis D. J., DelNido P. J., Koretsky A. P. Functional and energetic effects of the inotropic agents EMD-57033 and BAPTA on the isolated rat heart. Am J Physiol. 1995 Aug;269(2 Pt 1):C472–C479. doi: 10.1152/ajpcell.1995.269.2.C472. [DOI] [PubMed] [Google Scholar]
  14. Halstead J., Kemp K., Ignotz R. A. Evidence for involvement of phosphatidylcholine-phospholipase C and protein kinase C in transforming growth factor-beta signaling. J Biol Chem. 1995 Jun 9;270(23):13600–13603. doi: 10.1074/jbc.270.23.13600. [DOI] [PubMed] [Google Scholar]
  15. Harada K., Friedman M., Lopez J. J., Wang S. Y., Li J., Prasad P. V., Pearlman J. D., Edelman E. R., Sellke F. W., Simons M. Vascular endothelial growth factor administration in chronic myocardial ischemia. Am J Physiol. 1996 May;270(5 Pt 2):H1791–H1802. doi: 10.1152/ajpheart.1996.270.5.H1791. [DOI] [PubMed] [Google Scholar]
  16. Hashimoto E., Ogita T., Nakaoka T., Matsuoka R., Takao A., Kira Y. Rapid induction of vascular endothelial growth factor expression by transient ischemia in rat heart. Am J Physiol. 1994 Nov;267(5 Pt 2):H1948–H1954. doi: 10.1152/ajpheart.1994.267.5.H1948. [DOI] [PubMed] [Google Scholar]
  17. Kieser A., Weich H. A., Brandner G., Marmé D., Kolch W. Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene. 1994 Mar;9(3):963–969. [PubMed] [Google Scholar]
  18. Kihara Y., Grossman W., Morgan J. P. Direct measurement of changes in intracellular calcium transients during hypoxia, ischemia, and reperfusion of the intact mammalian heart. Circ Res. 1989 Oct;65(4):1029–1044. doi: 10.1161/01.res.65.4.1029. [DOI] [PubMed] [Google Scholar]
  19. Levy A. P., Levy N. S., Goldberg M. A. Post-transcriptional regulation of vascular endothelial growth factor by hypoxia. J Biol Chem. 1996 Feb 2;271(5):2746–2753. doi: 10.1074/jbc.271.5.2746. [DOI] [PubMed] [Google Scholar]
  20. Levy A. P., Levy N. S., Wegner S., Goldberg M. A. Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J Biol Chem. 1995 Jun 2;270(22):13333–13340. doi: 10.1074/jbc.270.22.13333. [DOI] [PubMed] [Google Scholar]
  21. Li J., Brown L. F., Hibberd M. G., Grossman J. D., Morgan J. P., Simons M. VEGF, flk-1, and flt-1 expression in a rat myocardial infarction model of angiogenesis. Am J Physiol. 1996 May;270(5 Pt 2):H1803–H1811. doi: 10.1152/ajpheart.1996.270.5.H1803. [DOI] [PubMed] [Google Scholar]
  22. Li J., Perrella M. A., Tsai J. C., Yet S. F., Hsieh C. M., Yoshizumi M., Patterson C., Endege W. O., Zhou F., Lee M. E. Induction of vascular endothelial growth factor gene expression by interleukin-1 beta in rat aortic smooth muscle cells. J Biol Chem. 1995 Jan 6;270(1):308–312. doi: 10.1074/jbc.270.1.308. [DOI] [PubMed] [Google Scholar]
  23. MacLellan W. R., Brand T., Schneider M. D. Transforming growth factor-beta in cardiac ontogeny and adaptation. Circ Res. 1993 Nov;73(5):783–791. doi: 10.1161/01.res.73.5.783. [DOI] [PubMed] [Google Scholar]
  24. Miller J. W., Adamis A. P., Shima D. T., D'Amore P. A., Moulton R. S., O'Reilly M. S., Folkman J., Dvorak H. F., Brown L. F., Berse B. Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am J Pathol. 1994 Sep;145(3):574–584. [PMC free article] [PubMed] [Google Scholar]
  25. Minchenko A., Bauer T., Salceda S., Caro J. Hypoxic stimulation of vascular endothelial growth factor expression in vitro and in vivo. Lab Invest. 1994 Sep;71(3):374–379. [PubMed] [Google Scholar]
  26. Pertovaara L., Kaipainen A., Mustonen T., Orpana A., Ferrara N., Saksela O., Alitalo K. Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fibroblastic and epithelial cells. J Biol Chem. 1994 Mar 4;269(9):6271–6274. [PubMed] [Google Scholar]
  27. Shalaby F., Rossant J., Yamaguchi T. P., Gertsenstein M., Wu X. F., Breitman M. L., Schuh A. C. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 1995 Jul 6;376(6535):62–66. doi: 10.1038/376062a0. [DOI] [PubMed] [Google Scholar]
  28. Sharma H. S., Wünsch M., Schmidt M., Schott R. J., Kandolf R., Schaper W. Expression of angiogenic growth factors in the collateralized swine myocardium. EXS. 1992;61:255–260. doi: 10.1007/978-3-0348-7001-6_40. [DOI] [PubMed] [Google Scholar]
  29. Shima D. T., Deutsch U., D'Amore P. A. Hypoxic induction of vascular endothelial growth factor (VEGF) in human epithelial cells is mediated by increases in mRNA stability. FEBS Lett. 1995 Aug 21;370(3):203–208. doi: 10.1016/0014-5793(95)00831-s. [DOI] [PubMed] [Google Scholar]
  30. Shweiki D., Itin A., Neufeld G., Gitay-Goren H., Keshet E. Patterns of expression of vascular endothelial growth factor (VEGF) and VEGF receptors in mice suggest a role in hormonally regulated angiogenesis. J Clin Invest. 1993 May;91(5):2235–2243. doi: 10.1172/JCI116450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Shweiki D., Itin A., Soffer D., Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992 Oct 29;359(6398):843–845. doi: 10.1038/359843a0. [DOI] [PubMed] [Google Scholar]
  32. Villarreal F. J., Dillmann W. H. Cardiac hypertrophy-induced changes in mRNA levels for TGF-beta 1, fibronectin, and collagen. Am J Physiol. 1992 Jun;262(6 Pt 2):H1861–H1866. doi: 10.1152/ajpheart.1992.262.6.H1861. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES