Age-related changes in cardiac expression of VEGF and its angiogenic receptor KDR in stroke-prone spontaneously hypertensive rats
We examined the age-related changes in cardiac expression of angiogenic molecules during the development of cardiac remodeling in stroke-prone spontaneously hypertensive rats (SHRSP) in comparison with those in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Vascular endothelial growth factor (VEGF) was highly upregulated in SHRSP aged 20 weeks compared with the same age of WKY, but it was downregulated at 40 weeks. On the other hand, KDR, an angiogenic receptor of VEGF, and endothelial nitric oxide synthase, which is important in the VEGF-mediated angiogenic pathway, were markedly downregulated in SHRSP from 20 weeks of age. Such age-related changes in their expression levels seen in SHRSP were quite different from those in SHR. In both SHR and SHRSP, transforming growth factor-β1 (TGF-β1) expression was increased with age, although SHRSP showed more marked upregulation. Cardiac remodeling in SHRSP was characterized by decreased coronary capillary density, cardiomyocyte hypertrophy, and cardiac fibrosis. We conclude that, in addition to overexpression of TGF-β1, which appears to play a pivotal role in promoting cardiac hypertrophy and fibrosis, a defect of the VEGF-KDR system could result in impaired physiologic coronary angiogenesis in SHRSP, contributing to cardiac deteroration associated with myocardial ischemia in this malignant hypertensive model.
Keywordscardiac remodeling coronary vessels endothelial nitric oxide synthase hypertension transforming growth factor-β1 vascular endothelial growth factor
Unable to display preview. Download preview PDF.
- 2.Okamoto K, Yamori Y, Nagaoka A: Establishment of the stroke-prone spontaneously hypertensive rat (SHR). Circ Res 33/34 (suppl I): I143–I153, 1974Google Scholar
- 7.Kim S, Ohta K, Hamaguchi A, Omura T, Yukimura T, Miura K, Inada Y, Ishimura Y, Chatani F, Iwao H: Angiotensin II type 1 receptor antagonist inhibits the gene expression of transforming growth factor-beta 1 and extracellular matrix in cardiac and vascular tissues of hypertensive rats. J Pharmacol Exp Ther 273: 509–515, 1995PubMedGoogle Scholar
- 9.Koyama T, Gao M, Batra S, Togashi H, Saito H: Myocyte hypertrophy and capillarization in spontaneously hypertensive stroke-prone rats. In: E.M. Nemoto, P. LaManna (eds.), Oxygen Transport to Tissue XVIII. Plenum Press, New York, 1997, pp 365–369Google Scholar
- 10.Ferrara N: Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am J Physiol 280: C1358–C1366, 2001Google Scholar
- 12.Jesmin S, Hattori Y, Sakuma I, Mowa CN, Kitabatake A: Role of ANG II in coronary capillary angiogenesis at the insulin-resistant stage of a NIDDM rat model. Am J Physiol 283: H1387–H1397, 2002Google Scholar
- 13.Ziche M, Morbidelli L, Choudhuri R, Zhang HT, Donnini S, Granger HJ, Bicknell R: Nitric oxide synthase lies downstream from vascular endothelial growth factor’s effect on the activation of protein kinase C, its isoforms, and endothelial cell growth. J Clin Invest 98: 2018–2026, 1997Google Scholar
- 14.Papapetropoulos A, Garcia-Cardena G, Madri JA, Sessa WC: Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells. J Clin Invest 100: 2567–2578, 1998Google Scholar
- 17.Batra S, Koyama T, Gao M, Horimoto M, Rakusan K: Microvascular geometry of the rat heart. Arteriolar and venular regions. Jpn Heart J 33: 817–828, 1992Google Scholar
- 20.Murohara T, Witzenbichler B, Spyridopoulos I, Asahara T, Ding B, Sullivan A, Losordo DW, Isner JM: Role of endothelial nitric oxide synthase in endothelial cell migration. Arterioscler Thromb Vasc Res 19: 1156–1161, 1999Google Scholar
- 23.Abe K, Tokumura M, Ito T, Murai T, Takashima A, Ibii N: Involvement of iNOS in postishemic heart dysfunction of stroke-prone spontaneously hypertensive rats. Am J Physiol 280: H668–H673, 2001Google Scholar
- 30.Nagineni CN, Samuel W, Nagineni S, Pardhasaradhi K, Wiggert B, Detrick B, Hooks JJ: Transforming growth factor-β induces expression of vascular endothelial growth factor in human retinal pigment epithelial cells: Involvement of mitogen-activated protein kinases. J Cell Physiol 197: 453–462, 2003PubMedGoogle Scholar