Restoration of coronary collateral growth in the Zucker obese rat:

Impact of VEGF and ecSOD


The metabolic syndrome (MS), a condition characterized by several risk factors for coronary artery disease, including obesity, is associated with endothelial dysfunction and oxidative stress. Because proper endothelial function is essential for signaling of certain growth factors (vascular endothelial growth factor, VEGF) we hypothesized that coronary collateral growth (CCG) is impaired in a model of the MS. To test this hypothesis, we stimulated coronary collateral growth in pre-diabetic Zucker obese fatty rats (OZR) and lean littermates (LZR) by using episodic, repetitive ischemia (RI: 40 s left anterior descending arterial occlusion, 24/d for 14 d). Myocardial blood flow (MBF, radioactive microspheres) was measured in the normal (NZ) and collateral-dependent (ischemic) zones (CZ); CCG was assessed as a ratio of CZ/NZ flow (unity represents complete restoration of CZ flow). In LZR, CZ/NZ ratio increased from 0.18 ± 0.03 to 0.81 ± 0.07 after RI (P < 0.05). In contrast, in OZR rats CZ/NZ did not increase after RI (0.15 ± 0.04 vs 0.18 ± 0.04). To rectify abrogated collateral growth in OZR, we employed VEGF gene therapy (VEGF-transduced, strained-matched, cultured vascular smooth muscle cells [cVSMCs], delivered intracoronary). VEGF therapy modestly but not significantly increased the CZ/NZ ratio after RI (0.16 ± 0.05 vs 0.33 ± 0.06). To facilitate VEGF signaling,we reduced oxidative stress by transducing cVSMCs with both ecSOD and VEGF. This increased the CZ/NZ flow ratio after RI to 0.52 ± 0.04 (p < 0.05 vs. OZR [(0.19 ± 0.04]) indicating partial restoration of collateral growth. Our results demonstrate that coronary collateral growth is impaired in a model of the metabolic syndrome and that growth factor gene therapy with VEGF is made far more effective when it is coupled to an intervention that reduces oxidative stress.

Key words

collateral growth gene therapy coronary circulation VEGF obesity 


  1. 1.
    Brzezinska AK, Lohr N, Chilian WM (2005) Electrophysiological effects of O2*- on the plasma membrane in vascular endothelial cells. Am J Physiol Heart Circ Physiol 289:H2379–H2386CrossRefPubMedGoogle Scholar
  2. 2.
    Chilian WM, Mass HJ, Williams SE, Layne SM, Smith EE, Scheel KW (1990) Microvascular occlusions promote coronary collateral growth. Am J Physiol Heart Circ Physiol 258: H1103–H1111Google Scholar
  3. 3.
    Feletou M, Vanhoutte P (2006) Endothelial dysfunction: a multifaceted disorder (The Wiggers Award Lecture). Am J Physiol Heart Circ Physiol 291(3):H985–H1002CrossRefPubMedGoogle Scholar
  4. 4.
    Focardi M,Dick GM, Picchi A, Zhang C, WMC (2007) Restoration of coronary endothelial function in obese Zucker rats by a low carbohydrate diet. Am J Physiol Heart Circ Physiol (Epub ahead of print)Google Scholar
  5. 5.
    Hattan N, Warltier D, Gu W, Kolz C, Chilian WM, Weihrauch D (2004) Autologous vascular smooth muscle cellbased myocardial gene therapy to induce coronary collateral growth. Am J Physiol Heart Circ Physiol 287:H488–H493CrossRefPubMedGoogle Scholar
  6. 6.
    Hughes GC, Annex B (2005) Angiogenic therapy for coronary artery and peripheral arterial disease. Expert Rev Cardiovasc Ther 3(3):521–535CrossRefPubMedGoogle Scholar
  7. 7.
    Jacobi J, Kristal B, Chezar J, Shaul SM, Sela S (2005) Exogenous superoxide mediates pro-oxidative, proinflammatory, and procoagulatory changes in primary endothelial cell cultures. Free Radic Biol Med 39(9):1238–1248CrossRefPubMedGoogle Scholar
  8. 8.
    Kobara M, Tatsumi T, Takeda M, Mano A, Yamanaka S, Shiraishi J, Keira N, Matoba S, Asayama J, M. N (2003) The dual effects of nitric oxide synthase inhibitors on ischemia-reperfusion injury in rat hearts. Basic Res Cardiol 98(5):319–328CrossRefPubMedGoogle Scholar
  9. 9.
    Konukoglu D, Serin O, Turhan M (2006) Plasma leptin and its relationship with lipid peroxidation and nitric oxide in obese female patients with or without hypertension. Arch Med Res 37(5):602–606CrossRefPubMedGoogle Scholar
  10. 10.
    Laukkanen MO, Leppanen P, Turunen P, Tuomisto T, Naarala J, S Y-H (2001) ECSOD gene therapy reduces paracetamol- induced liver damage in mice. J Gene Med 3(4):32–325CrossRefPubMedGoogle Scholar
  11. 11.
    Lee SU, Wykrzykowska JJ, Laham R (2006) Angiogenesis: bench to bedside, have we learned anything? Toxicol Pathol 34(1):3–10CrossRefPubMedGoogle Scholar
  12. 12.
    Lei Y, Haider HKh, Shujia J, ES. S (2004) Therapeutic angiogenesis. Devising new strategies based on past experiences. Basic Res Cardiol 99(2):121–132CrossRefPubMedGoogle Scholar
  13. 13.
    Lynch RE, Fridovich I (1978) Permeation of the erythrocyte stroma by superoxide radical. J Biol Chem 253(13):4697–4699PubMedGoogle Scholar
  14. 14.
    Martorana PA, Goebel B, Ruetten H, Koehl D, M. K (1998) Coronary endothelial dysfunction after ischemia and reperfusion in the dog: a functional and morphological investigation. Basic Res Cardiol 93(4):257–263CrossRefPubMedGoogle Scholar
  15. 15.
    Matsunaga T, Warltier DC, Weihrauch DW, Moniz M, Tessmer J, Chilian W (2000) Ischemia-induced coronary collateral growth is dependent on vascular endothelial growth factor and nitric oxide. Circulation 102(25):3098–3103PubMedGoogle Scholar
  16. 16.
    Nathoe HM, Koerselman J, Buskens E, van Dijk D, Stella PR, Plokker TH, Doevendans PA, Grobbee DE, PP; dJ, Group OS (2006) Determinants and prognostic significance of collaterals in patients undergoing coronary revascularization. Am J Cardiol 98(1):31–35CrossRefPubMedGoogle Scholar
  17. 17.
    Park F, Ohashi K, K. MA (2000) Therapeutic levels of human factor VIII and IX using HIV-1 based lentiviral vectors in mouse liver. Blood 96:1173–1176PubMedGoogle Scholar
  18. 18.
    Picchi A, Gao X, Belmadani S, Potter BJ, Focardi M, Chilian WM, Zhang C (2006) Tumor necrosis factor-alpha induces endothelial dysfunction in the prediabetic metabolic syndrome. Circ Res 99:69–77CrossRefPubMedGoogle Scholar
  19. 19.
    Serkova NJ, Jackman M, Brown JL, Liu T, Hirose R, Roberts JP, Maher JJ, CU N (2006) Metabolic profiling of livers and blood from obese Zucker rats. J Hepatol 44(5):956–962CrossRefPubMedGoogle Scholar
  20. 20.
    Simons M, Bonow RO, Chronos NA, Cohen DJ, Giordano FJ, Hammond HK, Laham RJ, Li W, Pike M, Sellke FW, Stegmann TJ, Udelson JE, Rosengart T (2000) Clinical trials in coronary angiogenesis: issues, problems, consensus: An expert panel summary. Circulation 102(11):E73–E86PubMedGoogle Scholar
  21. 21.
    Terada L (1996) Hypoxia-reoxygenation increases O2- efflux which injures endothelial cells by an extracellular mechanism. Am J Physiol 270(3 Pt 2):H945–H950PubMedGoogle Scholar
  22. 22.
    Toyota E, Warltier DC, Brock T, Ritman E, Kolz C, O’Malley P, Rocic P, Focardi M, Chilian WM (2005) Vascular endothelial growth factor is required for coronary collateral growth in the rat. Circulation 112:2108–2113CrossRefPubMedGoogle Scholar
  23. 23.
    Zachary I (2001) Signaling mechanisms mediating vascular protective actions of vascular endothelial growth factor. Am J Physiol Cell Physiol 280(6):C1375–C1386PubMedGoogle Scholar

Copyright information

© Steinkopff-Verlag 2007

Authors and Affiliations

  1. 1.Dept. of Physiology Louisiana State University Health Sciences CenterNew Orleans (LA)USA
  2. 2.Dept. of Pharmacology Cardiovascular Center of ExcellenceProgram in Gene Therapy Louisiana State University Health Sciences CenterNew Orleans (LA)USA

Personalised recommendations