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LETTER TO THE EDITOR

Vascular endothelial growth factor: angiogenesis, atherogenesis or both?

^a Cardiology Division, Department of Medicine, Innsbruck University, Anichstrasse 35, A-6020 Innsbruck, Austria

josef.dulak{at}uklibk.ac.at

Among the studies demonstrating the therapeutic efficiency of VEGF were reports suggesting the opposite (1,2). It took, however, several years until stronger evidence was obtained. In recent issues of JACC (1) and Nature Medicine (2) Celletti et al. (1,2) have published data demonstrating that VEGF promotes atherogenesis. They used two animal models: double knockout mice (apoE/apoB100), in which spontaneous atherosclerosis was aggravated by a single injection of a low dose of VEGF protein (2), and cholesterol-fed rabbits, which when treated by VEGF developed larger plaques (1,2). The investigators showed that VEGF increased the total number of blood and plaque monocytes/macrophages and enriched the pool of circulating CD34+/flk–1+ progenitor cells that might enhance neoangiogenesis (1,2).

Those intriguing studies raise many questions. Particulary, it remains to be established how those experimental data relate to the results of the clinical trials with angiogenic growth factors, which so far did not report any significant side effects. In our opinion the results presented by Celletti et al. (1,2) force us also to reinvestigate the role of VEGF using more basic approaches. One of the crucial aims will be to understand the mechanisms governing VEGF synthesis and angiogenic activity in normal and atherosclerotic vessels.

We have recently demonstrated that nitric oxide (NO) enhanced VEGF synthesis in vascular smooth muscle cells (VSMC) (3,4). Nitric oxide synthesis is inhibited by modified low-density lipoprotein (LDL), which is elevated in atherosclerosis (5). However, this does not result in attenuation of VEGF production. In fact, lipid components of modified LDL enhanced VEGF expression in VSMC independently of their inhibitory effect on the generation of NO by inducible nitric oxide synthase (iNOS) (5).

Those data, which are supported by others (6), show that different factors can enhance VEGF in the vessel wall and initiate or promote atherosclerosis. In fact, VEGF is strongly expressed in the plaque (7,8). Thus, probably the inhibition, but not the supplementation, of VEGF has to be regarded for the treatment of atherosclerosis. Application of a strong antiangiogenic treatment might not be a good option for patients with already impaired blood supply and developing plaques. However, an interesting, safer alternative might already exist. The statins, inhibitors of HMG-CoA reductase, which efficiently decrease cholesterol levels, may also influence VEGF production by interrupting the lipid-mediated enhancement of VEGF production. In our recent study (9) we have demonstrated that atorvastatin therapy for two months decreased VEGF plasma levels in hypercholesterolemic patients. Additionally, we have shown that lovastatin decreased both basal and cytokine-induced VEGF production, and it also diminished the iNOS-mediated cytokine-induced NO generation (Fig. 1). Thus, statins may modulate VEGF level including lipid-dependent and lipid-independent pathways.

View larger version (35K): [in this window] [in a new window]   Figure 1 Lovastatin decreases cytokine-induced nitric oxide (NO)-generation and vascular endothelial growth factor (VEGF) synthesis in vascular smooth muscle cells (VSMC). Rat thoracic aorta VSMC were treated for 24 h with lovastatin (10 µmol/liter) and/or interleukin (IL)-1ß (10 ng/ml) and tumor necrosis alpha (TNF)- (10 ng/ml). The VEGF protein and nitrite concentrations were determined in media after 24 h of culture, using an ELISA kit (R&D System) and the Griess reagent method, respectively. Only background amounts of nitrites, not derived from inducible NO synthase activity, have been detected in cells not treated with cytokines. Mean ± SD (three independent experiments), analysis of variance followed by the Scheffè test. *p < 0.02 vs. control; #p < 0.01 vs. IL/TNF. Lovastatin also decreased VEGF synthesis in human VSMC (not shown).

	References

Top References

 
1. Celletti FL, Hilfiker PR, Ghafouri P, Dake MD. Effect of human recombinant vascular endothelial growth factor₁₆₅ on progression of atherosclerotic plaque. J Am Coll Cardiol. 2001;37:2126–2130[Abstract/Free Full Text]

2. Celletti FL, Waugh JM, Amabile PG, Brendolan A, Hilfiker PR, Dake MD. Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nat Med. 2001;7:425–429[CrossRef][Medline]

3. Dulak J, Jozkowicz A, Dembinska-Kiec A, et al. Nitric oxide induces the synthesis of vascular endothelial growth factor by rat vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2000;20:659–666[Abstract/Free Full Text]

4. Jozkowicz A, Cooke JP, Guevara I, et al. Genetic augmentation of nitric oxide synthase increases the vascular generation of VEGF. Cardiovasc Res. 2001;51:773–783[Abstract/Free Full Text]

5. Dulak J, Józkowicz A, Dichtl W, et al. VEGF synthesis in vascular smooth muscle cells is enhanced by 7-ketocholesterol and lysophosphatridylcholine independently of their effect on nitric oxide generation. Atherosclerosis. In press.

6. Inoue M, Itoh H, Tanaka T, et al. Oxidized LDL regulates vascular endothelial growth factor expression in human macrophages and endothelial cells through activation of peroxisome proliferator-activated receptor-. Arterioscler Thromb Vasc Biol. 2001;21:560–566[Abstract/Free Full Text]

7. Inoue M, Itoh H, Uedea M, et al. Vascular endothelial growth factor (VEGF) expression in human coronary atherosclerotic lesions: possible pathophysiological significance of VEGF in progression of atherosclerosis. Circulation. 1998;98:2108–2116[Abstract/Free Full Text]

8. Chen YX, Nakashima Y, Tanaka K, Shiraishi S, Nakagawa K, Sueishi K. Immunohistochemical expression of vascular endothelial growth factor/vascular permeability factor in atherosclerotic intimas of human coronary arteries. Arterioscler Thromb Vasc Biol. 1999;19:131–139[Abstract/Free Full Text]

9. Alber HF, Dulak J, Hügel H, Pachinger O, Schwarzacher SP, Weidinger F. Atorvastatin reduces the blood levels of vascular endothelial growth factor (VEGF) in patients with coronary artery disease (abstr). J Am Coll Cardiol. 2001;37(Suppl A):1093–1173[Abstract/Free Full Text]

This article has been cited by other articles:

				J. Dulak and A. Jozkowicz Nitric oxide and angiogenic activity of endothelial cells: direct or VEGF-dependent effect? Cardiovasc Res, December 1, 2002; 56(3): 487 - 488. [Full Text] [PDF]

				H. Franz Alber, J. Dulak, M. Frick, W. Dichtl, S. Paul Schwarzacher, O. Pachinger, and F. Weidinger Atorvastatin decreases vascular endothelial growth factor in patients with coronary artery disease J. Am. Coll. Cardiol., June 19, 2002; 39(12): 1951 - 1955. [Abstract] [Full Text] [PDF]

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